Dementia With Lewy Bodies Dlb Biology Essay


Dementia with Lewy-bodies (DLB) is second most common type of Dementia in ageing populations with its prevalence of 30% in Dementia patients being second only to Alzheimer’s disease, and an overall incidence rate of 0.1% in the general population (McKeith et al. 1996, Zachai et al. 2005). In terms of clinical pathology there is no difference between the end-stage symptoms of Parkinson’s Disease Dementia (PD) and DLB therefore the two share similar symptoms in the patients such as motor dysfunction (bradykinesia, movement disorders and rigidity in the body), degradation of cognitive abilities, hallucinations and susceptible to mood disorders. Although these symptoms may not necessarily be present in the early stages, they become more apparent as the disease progresses and are always present in the later stages of both diseases. Although DLB and PD are pathologically very similar, it is important to differentiate between the two as patients with DLB have very severe reactions to neuroleptic drugs as compared to patients with PDD. Similarly, patients with DLB show a very positive response when anticholinesterase drugs are administered compared to patients with PDD. The "one year rule" is a criterion that separates DLB from Parkinson’s Dementia; it states that if a patient develops dementia within one year of developing PDD symptoms then we classify the disease as DLB, however if more than one year elapses between the onset of Parkinsonian symptoms and dementia then we classify it as PD. In other words DLB is early-onset dementia and PDD is late-onset dementia in relation to the onset of Parkinsonian symptoms.

The aim of this review is to provide a suitable introduction to the variety of the genes involved in DLB as well a brief summary of Lewy Body structure/formation and the diagnostic criteria of DLB.


For accurate diagnosis of DLB, clinical features are separated into different categories to give simple and systematic criteria to differentiate between DLB and PDD. Features are divided into Central, Core and Suggestive features, with the number and combination of core and suggestive features determining whether the diagnosis is of "probable dementia" or "possible dementia". One core feature indicates "possible DLB" whereas two core features indicate "probable DLB". One core feature with one or more suggestive features can allow the diagnosis of "probable DLB", however suggestive features with no core features can only diagnose "possible DLB". Central features are features without which a diagnosis of dementia cannot be made as they form the integral characteristics of the disease (McKeith et al. 2005).

Central Features

The central feature of DLB is a progressive cognitive decline which resulting in a decreased attention span due to deficiencies in the cortical and subcortical regions of the brain. This decline must significantly impact day to day living for it to be classed as a central feature. This decline becomes more apparent the disease progresses and can be differentiated from AD due to the decrease in recognition ability and short-medium term recall being comparatively less in comparison to AD and the decrease in verbal communication and task performance being much more pronounced. However there is little distinction between the extent of cognitive decline in PDD and DLB (Mega et al. 1996, Luis et al. 1999)

Core features

One of the most useful indicators of a positive diagnosis of DLB is recurring visual hallucinations present early in the onset of the diseases.

Another core feature of DLB is fluctuations in cognitive abilities of the patient with periods of lower alertness ("episodes of muddled thinking") compared to normal function. This is often more difficult to diagnose in clinical practice as great detail is required from the information received from the carer to make an accurate diagnosis. The Clinical Assessment of Fluctuation is used by experienced clinicians whereas the One Day Fluctuation scale and Mayo Scales are designed to be used by less experienced assessors or care-giver (Walker et al. 2000, Ferman et al. 2004).

Another major core feature is the presence of extrapyramidal motor features that is characteristic of Parkinson’s disease, resulting in similar visible impairments of overall movement and facial expressions. This is normally assessed by the Unified PD Rating Scale. However it is important to note that extra-pyramidal signs are not recorded in up to 25% of DLB cases, thereby demonstrating that the absence of PD signs does not necessarily mean absence of DLB (Ballard et al. 1997).

Suggestive Features

A patient presented with a history of sensitivity to D2 receptor inhibiting neuroleptic drugs would indicate the presence of DLB provided that the aforementioned core features are present. Another suggestive feature is the dysfunction of the nigrostriatal dopamine pathway which can be detected through Dopamine Transporter Imaging, a useful way of distinguishing between AD and DLB (McKeith et al. 1992).

The presence of REM Sleep Behaviour disorder and abnormal drowsiness during the day is often indicative of PD and DLB, can be present years before the onset of the symptoms and is rarely associated with other neurodegenerative disorders making it a distinguishing suggestive feature (Boeve et al. 2003).

Supporting features and Exclusion Features

Supporting features that should be taken into account when making a diagnosis of DLB include: incontinence, constipation, cardiovascular problems and impotence. These can usually be identified by the carer responsible for the patient and although are not enough to diagnose for DLB on their own they may be useful in the overall diagnosis and clinical evaluation of a patient with DLB.

Certain exclusion features must be taken into account by the clinician so as not to misdiagnose DLB. For example the presence of a cerebrovascular disease, mental disorders and first onset of parkinsonian symptoms in late stage dementia all render the chances of dementia to be less likely as they explain the clinical presentations that may be mistaken for DLB (McKeith et al. 2005).

Lewy Bodies

Lewy Bodies are spherical intra-cytoplasmic inclusions 10-30um in diameter that are found in the dopaminergic neurones substantia nigra pars compacta, in the noradrenergic neurones in the locus coeruleus and in the cholinergic neurones of the nucleus basalis of Meyrnert (Pollanen et al. 1993, Forno et al. 1996). Lewy Bodies consist of ALPHA-synuclein, the ALPHA-synuclein binding protein synphelin-1, ubuiquitin, torsinA, HSP70/90 heat shock proteins, neurofilaments and an ubuiquitin-proteosome system (Schmidt et al. 1991, Spillanti et al. 1997). These proteins are involved in the nitration, ubuiquitination, phosphorylation, oxidisation, transport and folding of proteins as well as having roles in the degradation pathways for damaged/misfolded protein (Good et al. 1998, Fujiwara et al. 2002). Lewy bodies occur in DLB, PD and AD, and are in fact detected in the substantia nigra of up to 15% of patients that are over the age of 65 who are not suffering from a Lewy Body related disease.

The formation of Lewy Bodies is thought to be related to aggresomes and centrosomes; centrosomes are microtubule structures that co-ordinate microtubule formations during cell mitosis express gamma tubulin, proteasomes and pericentrin (Stearns et al. 1991, Doxsey et al. 1994). Aggresomes are formed from centrosomes when protein aggregates accumulate in the centrosome and ubuiquitin-proteosome system proteins are recruited to remove them. The accumulation of these various proteins forms an insoluble expanded centrosome-like structure called the aggresome which functions as a site for the degradation of abnormal and toxic proteins (Johnston et al. 1998). There are various links between aggresomes and Lewy Bodies: both have a similar distribution of gamma tubulin and pericentrin, they share many of the component proteins found in ubuiquitin-protease system and both have a protective role against cytotoxic proteins, although this may be more true of aggresomes than Lewy Bodies (McNaught et al. 2002). The process of Lewy Body formation begins with oxidative stress that is typical in PD and DLB resulting in free-radical damage to the ubiquitin-protease system components responsible for protein degradation resulting in an overall increase in un-degraded protein aggregates (Sitte et al. 2000). These series of events result in the transformation of centrosomes to aggresomes as ubuiquitin-protease system components are transported to the centrosome along with the unwanted protein aggregates. If these protein aggregates are successfully removed via aggresome mediated proteolysis the aggresome may recede, however if the removal is not successful the expansion of the aggresome continues to grow and expand into structures that we recognize as Lewy Bodies (Taylor et al. 2003). However it is important to note that Lewy Bodies act as pathological markers for DLB and PD and may not have any negative effect on neuronal function and may not be the cause of nigrial neurodegeneration (Ishihara et al. 2002). Their involvement in the removal of cytotoxic proteins implies that they are a protective measure/delaying mechanism against neuronal death/ cell apoptosis, a point demonstrated by the fact that neuronal degeneration is seen to occur in cases where there are no Lewy Bodies present (Van Duinen et al. 1999).

Genetics of DLB

Genes implicated in Lewy Body Disease


The SNCA gene encodes for Alpha Synuclein which is a protein found in neurones/neuronal synapses and has strong associations with PD and DLB pathogenesis as it is a key component of Lewy bodies (Giasson et al. 2000). The gene itself is spans 117kb, is found on chromosome location 4q1, contains around 6 exons and is activated by an upstream repeat (Touchman et al. 2001). The gene has been shown to be susceptible to duplication and triplication mutations with the former occurring due to unequal intra-allelic segmental duplication or intra-allelic recombination, with the latter occurring to both intra-allelic duplication and recombination (Ross et al. 2008). The duplications and triplications resulted in PD and DLB phenotypes, and the severity of the phenotypes would be according to the severity of the gene dosage; for example a higher SNCA copy number would result in a much severe phenotype (Ibanez et al. 2009).

The Alpha Synuclein protein itself is found primarily in neurones and their pre-synaptic terminals as evidenced by immunohistochemistry and immunoblotting; antibodies to specific tyrosine residues in alpha synuclein were targeted (Giasson et al. 2000). It’s localization to the synaptic axon terminals in neurones is because it is a transport protein that plays a role in the regulation of vesicles involved in neurotransmitter synaptic release/synaptic transmission as well as possibly being involved in the regulation of dopamine in specific (Spillanti et al. 1997). It may also play a role in the post synaptic recycling of vesicles as it is shown to have regulatory interactions with Phospholipase D. This would result in disrupted dopamine neurotransmission, accumulation of dopamine in the synaptic cleft and subsequent increase in oxidative stress in the event of a SNCA mutation (Lotharius and Brundin. 2002). As stated earlier, Alpha Synuclein is a key component of Lewy Bodies and other inclusions that play a role in neurodegenerative disease due to overexpression and subsequent abnormal aggregation (Giasson et al. 2000). Additionally, aggregation of alpha-synuclein in neurones can result in neuronal apoptosis, but only in dopaminergic neurones which results in misregulation of DA. Thus there are higher amounts of alpha synuclein protein complexes in the substantia nigra, which contains a high concentration of DA neurones, in patients with PD as compared to healthy controls. It is interesting to note that Alpha synuclein does not induce apoptosis in the neurones of the human cortex, but in fact it protects them from apoptosis (Xu et al. 2002).

Before exploring the different types of alpha synuclein mutations and their implications in disease, it is useful to cover the various interactions of wildtype alpha synuclein and discuss their possible contributions to the pathogenesis in neurodegenerative disease.

Alpha synuclein interacts with microtubule associated protein tau/MAPT which resulted in the formation of filamentous inclusions through fibrillization of the proteins. This fibrillization is a characteristic pathological feature in patients with neurodegenerative disease, whereas healthy patients normally have these proteins in an unfolded conformation. This mechanism of formation of inclusions is relevant to both PD and DLB (Giasson et al. 2003).

Alpha synuclein interacts with both saturated and polyunsaturated fatty acids to affect the levels of soluble alpha synuclein oligomers in the brain. Saturated fatty acids lower the amount of these soluble oligomers whereas polyunsaturated fatty acids increased the levels of the soluble oligomers. The formation of these oligomers eventually leads to the aggregation of insoluble alpha synuclein that is associated with the formation of inclusions that is associated with DLB and PD (Sharon et al. 2003).

The inhibition of SIRT2 results in an attenuation of alpha synuclein toxicity which implies that SIRT2 enhances the toxicity of Alpha Synuclein and increases the apoptosis of dopaminergic neurones (Outeiro et al. 2007)

Synphilin-1 is a protein that interacts with alpha synuclein which results in the formation of Lewy bodies/inclusions when parkin is also expressed (Chung et al. 2001).

KLK6 is serine protease neurosin which is localized to Lewy bodies and other inclusions. When challenged with oxidative stress the mitochondria releases neurosin which reduces the amount of alpha synuclein monomer available for polymerization as well as causing an increase in fragmented alpha synuclein through degradation which further inhibits polymerization. This may be a mechanism by which a cell regulates the amount of alpha synuclein in a cell that is available for aggregation and formation of inclusions. Inhibition or dysfunction of neurosin may therefore result in an increase in lewy body/inclusion formation in neurodegenerative disease (Iwata et al. 2003).

SIAH1 is a ubiquitin ligase that forms a complex with UBCH8 and targets wildtype Alpha Synuclein for degradation via ubiquitination. However SIAH1 cannot ubiquitinate mutated forms of alpha synuclein such as A30P and in facts increases the rate of aggregation of alpha synuclein. As SIAH1 is most often localized to inclusions (such as lewy bodies) in the substantia nigra, its interaction with both wildtype and mutated forms of Alpha Synuclein is strongly associated with the pathogenesis of DLB and PD.

The phosphorylation of Alpha Synuclein is a key mechanism in the formation of Lewy Bodies in the brain; when wild type alpha synuclein is phorosphorylated at the ser129 position it is targeted for transport to lewy bodies resulting in an increased rate of formation. This is important as it may possibly implicate the deregulation of kinases in an increased rate of formation of lewy body-like inclusions in neurodegenerative disease (Anderson et al 2006).

Both GBA and PARKIN are known to interact with wild type Alpha Synuclein however these interactions are covered in detail in the gene’s respective sections in the review.

SNCA is subject to various mutations that result in the formation of the pathological features of DLB and PD.

The most prominent of these mutations is the A53T mutation. The A53T missense mutation is an Ala-to-thr substitution which is a result of a nucleotide 209 Guanine to Adenine transition and this is strongly associated with autosomal dominant Parkinson’s disease. On alpha synuclein there is a sequence of 11 amino acids that exists as a series of seven imperfect repeats and the A53T mutation occurs in a segment between repeat 4 and repeat 5. The mutation has also been known to generate a novel restriction site in SNCA (Polymeropoulos et al. 1997). In initial studies there was a failure to find any link between the A53T mutation and PD in patients (Vaughan et al. 1998, Ho and Kung 1998, Farrer et al. 1998) however eventually studies began to link the presence of A53T to PD and its symptoms such as rigidity, bradykinesia, a decline in cognitive fuction and degeneration of neurones in the brainstem and subtantia nigra (Polymeropolous et al. 1997, Athanassiadou et al. 1999, Spira et al. 2001).

The A30P mutation is another very important mutation that is the result of a Guanine88 to Cytosine transversion at exon 3 in SNCA which results in an ala30-to-pro substitution in alpha synuclein which is strongly associated with PD. The mutation was discovered when screening for the A53T mutation in PD patients and the mutation was absent in the control subjects (Kruger et al. 1998). Like the A53T mutation, the main features of PD were present and the patients responded favourable to treatment with L-DOPA (Seidel et al. 2010).

Studies done on both the A53T and A30P mutations showed that the formation of alpha synuclein aggregates via fibrillization was accelerated by both mutations compared to the formation in wild type. In vitro, the A53T mutation would take 100 hours to form aggregates, the A30P mutation would form an aggregate in 180 hours and the wild type would take the longest time to form the aggregate at 280 hours. This in vitro experiment shows the large role that these two mutations have in PD pathogenesis (Nahri et al. 1999). Further in vitro studies on the role of these mutations in the fibrillization of alpha synuclein monomers found that fibrillization occurred more rapidly with the A30P monomers and the fastest with the A53T monomers when compared to the wild type. This again gave a valuable insight to the role of these mutations in the progression of PD pathology (Conway et al. 2000). An in vitro study was carried out where A30P expressing PC12 cells were exposed to a protease inhibitor and were observed to be more susceptible to caspase3/9 mediated apoptosis and showed a marked decrease in proteosomal function, although there was no presence of toxicity. This showed a novel mechanism by which apoptosis of neurones could occur in cells expressing A30P mutations which is linked to decreased proteasome activity (Tanaka et al. 2001). It has been shown that in vitro expression of A30P and A53T mutations have increased the formation of beta amyloid protofibrils that are associated with PD and Alzeihmers disease; These protofibrils result in pores forming in the cell membrane making it more permeable and thus weakening it’s overall integrity making it more susceptible to apoptosis (Lashuel et al. 2002).

An important mutation that is associated with Lewy Body Dementia is the Guanine188 to Adenine transition in SNCA which results in the glu46-to-lys substitution known as E46K, which produced a specific form of twisted filaments. When compared to the A30P, A53T and wildtype, the E46K mutant shows comparatively a much greater binding to liposomes and shows a greater rate of filament formation than wild type and A30P however not as much as A53T. It is worth noting that A30P produced the most amounts of filaments in the in vitro study. The role of the mutation in the formation of filaments highlights an important mechanism for the formation of Lewy Bodies, especially if the gene expressed with A53T or A30P mutations as well (Choie et al. 2004).

As discussed before, the duplication and triplication mutations in SNCA play an important role in the pathogensis of PD and DLB. The duplication mutation is linked to both autosomal dominant PD and DLB, whereas the triplication mutation is primarily linked to autosomal dominant PD alone. The heterozygous duplication of SNCA has been shown to cause the symptoms of autosomal dominant PD without the symptoms dementia in patients in various studies (Chartier-Harlin et al. 2004, Ibanez et al. 2004), however in other studies patients have shown symptoms typical to both PD and DLB with dementia developing a few years after the onset of PD (Nishioka et al. 2006, Fuchs et al. 2007, AHn et al. 2008, Uchiyama et al. 2008).

The triplication mutation of SNCA is associated with autosomal dominant PD; the triplication contains around 17 genes which result in double the gene dosage of SNCA due to multiple copies of it being expressed (Singleton et al. 2003). The increased expression results in greater amounts of SNCA in blood, brain tissue and overall alpha synuclein aggregation (Miller et al. 2004). The stronger the gene dosages are, the more rapid the progression of the disease and exceptionally severe symptoms have been reported as a result of tandem multiplications, as in the presence of duplication and triplication mutations (Farrer et al. 2004, Fuchs et al. 2007).


The LRRK2 gene is 144kb in length, contains 5 functional domains and is mapped to chromosome 12q12. The functional domains of LRRK2 are; ANK+LRR an ankyrin and leucine rich repeat located at the N-terminal, ROC which is a GTPase domain involved in kinase activity, COR Ras C-terminal domain, MAPKKK domain and WD40 repeats. Mutations that occur in the ROC, COR and MAPKKK domain are considered to be a major cause of PD and Lewy Body Formation (Ross et al. 2006, Gandhi et al. 2008).

One of the most common mutations that is implicated in PARK8 inherited PD is the gly2019-to-ser/G2019S substitution which occurs as a result of a heterozygous transition in exon 41 (Di Fonzo et al. 2005). This substituted motif is integral to the proper functioning of human kinase proteins and its mutation has been linked to Lewy Body formation, loss of neurons in the Locus Coerulus and substantia nigra, PD and general neural degeneration in multiple family studies across populations in different countries (Giasson et al. 2006, Lesage et al. 2005, Kachergus et al. 2005, Ross et al. 2006). Unlike the SNCA gene, there is no dosage dependent effect seen on the phenotype as populations that are homozygous for the mutations are clinically identical to populations that are heterozygous thus implying that there is perhaps a threshold of gene expression that needs to be exceeded or there is a dominant negative effect mechanism in place (Ishihara et al. 2006).

Another mutation implicated in PD is the arg1441-to-cys substitution that occurs in the ROC domain of LRRK2 and has mostly been implicated in increasing protein kinase activity. (Zimpirch et al. 2004, West et al. 2006). Although mouse models with knock-in R1441C mutations showed no direct dopaminergic degeneration they did report reduced transmission function of the dopaminergic D2 receptor, altered locomotor activity when exposed to amphetamines and inhibited release of catecholamines epinephrine when subjected to a stimulus. These signs are potentially linked to future degeneration of dopaminergic neurones (Tong et al. 2009).

It is suggested the LRRK2 and ALPHA-synuclein share the same pathogenic pathway with overexpression of LRRK2 with expression of A53T AS leading to increased levels of ALPHA-synuclein aggregation and thereby causing extensive neurodegeneration. Additionally Lewy Bodies resulting from LRRK2 expression contain ALPHA-synuclein and ubiquitin. It is suggested that the accumulation of proteins is a result of a malfunction of the Ubiquitin Protease System which results in increased levels of ALPHA-synuclein, ubiquitin and tau due to impaired clearance of the aggregates (Lichtenberg et al. 2011).

PINK1 and DJ-1

PINK1 (PTEN-induced putative kinase 1) is a gene 1.8kb in length that encodes for a mitochondrial serine/threonine kinase which plays a major role in preserving mitochondrial integrity and in the removal of damaged mitochondria (Valente et al. 2004, Poole et al. 2008). Although it was primarily homozygous mutations of PINK1 that were implicated in early onset autosomal recessive PD/PARK6 (Valente et al. 2004) it has been shown that heterozygous mutations can also be a risk factor in PD (Abou-Sleiman et al. 2006).

DJ-1 is a 24kb oncogene mapped to chromosome 1p36 (Bonifati et al. 2003) that has been shown to interact with the MAPT gene to result in the formation of taupathies (Rizzu et al. 2004) as well as interacting with parkin (product of the PARK2 gene) when in its mutant form to increase the stability of DJ-1 mutants in the cell and prevents them from being ubiquinated. It is possible that this increased stability is the explanation of higher levels of DJ-1 in insoluble fractions that are obtained from the cingulate cortex of patients with PD/DLB. This implies that either there is increased expression of the DJ-1 or improved stability as a result of the aforementioned interactions (Moore et al. 2005). However there does not seem to be any interaction between DJ-1 and ALPHA-synuclein (Neumann et al. 2004).

Mutations in both DJ-1 and PINK1 have been implicated in a digenic form of PD where the mutated DJ-1 gene appeared to stabilise the mutated and wild type PINK1 gene resulting in the symptoms normally associated with autosomal recessive early onset PARK6 PD; instability of posture, bradykinesia, resting tremor, general rigidity, sensitivity to levodopa and an asymmetric onset due to akinesia in limbs. The causes for this digenic form of PD were missense mutations in both PINK1 and DJ-1 were the mutations were seen to work together to significantly increase the risk of apoptosis in human neuroblastoma cells compared to cells that expressed either of the genes individually.


The PARK2 gene is found at location 6q26 on the human chromosome and it codes for the PARKIN protein, an E3 ubuiqitin ligase 465aa in length which plays a functional role in protein and mitochondria degradation (Kitada et al. 1998, Yoshii et al. 2011). Mutation and dysfunction of PARKIN has been associated with autosomal recessive early onset Parkinsons Disease and PARKIN itself has been shown to interact with a wide variety of other proteins such as alpha-synuclein, LRRK2 and PAELR to result in neurodegeneration. The PARK2 gene itself spans 1380kb with regions that contains regions rich in GC and CpG in the promoter regions, introns and exons as well as regulatory regions such as sites for the binding of SP1.

PARKIN, with the exception of a few mutated isoforms, is usually homogenously distributed in the cytoplasm and is expressed in most neuronal cell bodies with a few exceptions (Huynh et al. 2000). The mutated isoforms produced inclusions as aggresomes in the cytoplasm and the nucleus which may be linked to the formation of Lewy Bodies, although there is no direct localization of PARKIN to Lewy bodies observed (Cookson et al. 2003). PARKIN functions primarily as a ubuiquitin ligase and interacts with various conjugating proteins such as UBCH8 and UBE2L3 in order to carry out its function (Kitada et al. 1998, Shimura et al. 2000). However PARKIN has a very wide and complex variety of interactions with various other proteins that must be covered in reasonable detail to understand its role in PD.

Alpha-Synuclein is normally ubiquitinated by PARKIN which is mediated by PARKIN-UBCH7 enzyme interactions. In these interactions a 22kd form of alpha-synuclein called alpha-Sp22 would be bound to PARKIN and UBCH7 which would result in the formation of a complex that would degrade the alpha-Sp22. However mutated PARKIN would result in no binding/interactions between it and alpha-sp22 thereby resulting in a large accumulation of unubiquinated alpha-sp22 in the brain of PD patients. This accumulated protein would then possibly go on to form inclusions and thereby result in PD/DLB pathology (Shimura et al. 2001).

LRRK2 is itself strongly associated with PD however it has limited interaction with other PD associated genes with the exception of PARKIN. LRRK2 specifically interacted with PARKIN Ring2 domains via its own COR domain. Although overexpression of LRRK2 caused by mutations would increase the amount of protein aggregates, the co-expression of both LRRK2 and PARKIN would result in a much larger increase in ubiquitinated protein aggregates. This interaction combined with the interaction of PARKIN with Alpha-sp22 and synphilin-1 supports the theory that an ubiquitin protease pathway plays a key part in the development of PD pathology (Smith et al. 2005).

Synphillin-1 is a Synuclein-alpha-interacting-protein (SNCAIP) that is found in lewy bodies that, when overexpressed, can bind to alpha-synuclein to result in the formation of lewy bodies. PARKIN can interact with both Alpha-synuclein and synphilin-1 to result in the formation of lewy bodies/inclusions, and is thought to play a key role as dysfunctional mutations in PARKIN result in disruption in the formation of protein aggregates (Chung et al. 2001).

PINK-1 is normally involved in the recruitment of PARKIN to damaged mitochondria to result in their degradation and removal. However mutations associated with PD can disrupt this process at a number of steps; For example mutations in either PINK1 or the PARK2 gene can result in disruption of the removal of damaged mitochondria due to the need for PINK1 to assist the translocation of PARKIN to the area of mitochondrial damage. Furthermore PINK1 appears to regulate the function of PARKIN through phosphorylation, therefore a dysfunction in PINK1 would lead to impaired ubiquitination by PARKIN. PINK1 is therefore an example of an indirect effect/interaction on PARKIN function, as opposed to direct mutation of PARKIN, possibly playing a role in the neurodegeneration seen in PD. (Sha et al. 2010, Narendra et al. 2010, Geisler et al. 2010).

PAELR is a G-protein coupled receptor that is associated with PARKIN that is localized to the hippocampus and cerebellum. When it is overexpressed it is ubiquitinated by PARKIN and its UBCH7/UBE2L3 conjugates and targeted for proteosomal degradation. Insoluble PAELR can accumulate in the brains of those affected with early onset PD resulting in neurodegeneration thereby highlighting the importance of the key role that PARKIN plays in PAELR regulation (Imai et al. 2001).

DJ-1 is a key gene involved in early onset autosomal recessive PD (PARK7), however there are DJ1 mutants that interact with PARKIN to result in increased stability of the mutant isoforms rather than the expected PARKIN mediated ubiquitination. This interaction is further increased in the presence of oxidative stress, thereby implying a common pathway through which DJ1 and PARKIN cause PD pathogenesis.

CDK5 and CSNK1A1 are kinases that deactivate PARKIN by phosphorylation on the S101, S127 and S378 sites which would ultimately result in aggregation of the deactivated protein. The deactivation of PARKIN through phosphorylation represents a disruption in the ubuiquitin-proteosome pathway that may be associated with PD (Rubio de la Torre et al. 2009)

Dopamine is prone to oxidization into dopamine quinone which has the ability to interact with and modify PARKIN. The covalent binding of endogenous dopamine to PARKIN results in the inhibition of the proteins E3 ligase function and renders the protein completely insoluble. This inactivated and modified parkin is then free to aggregate in the brain of patients with PD and is a possible mechanism of the loss of DA neurones in the Sn region of the brain (La Voie et al. 2005).

S-Nitrosylation of PARKIN is a modification rather than an interaction but is important nonetheless as it is postulated that it is a key regulatory mechanism for PARKIN activity. The S-nitrosylation of PARKIN initially increases ligase activity resulting in autoubiquitination of PARKIN which thereby results in the activity of PARKIN beginning to decrease. The implication of the decrease in ligase activity is that the activity itself is in fact protective against oxidative stress; an overexpression of wild type PARKIN has shown to decrease the overall number of reactive oxygen species/toxic free radicals and inhibit activation of the MAPK8/caspase pathway which leads to cell apoptosis in DA neurones, a typical feature of neurodegenerative disease. These protective effects are lost if the functionality of PARKIN is altered due to mutation or autoubiquitination via S-nitrosylation. Thus S-nitrosylation is important for the overall understanding of free radical toxicity and cellular apoptosis in DA neurones in neurodegenerative disease. (Yao et al. 2004, Chung et al. 2004, Lipton et al. 2005, Chung et al. 2005)

p38 is a tRNA synthetase co-factor encoded by the JTV1 gene that is ubiquitinated and degraded by wildtype PARKIN under normal circumstances. If this degradation is not possible due to mutation/truncation in PARK, the increased expression of p38 can result in the formation of aggresome inclusions which ultimately leads to cell apoptosis. As p38 expression has been found to be significant in Lewy bodies and DA neurones in PD, the regulatory interaction between p38 and PARKIN is important in PD pathogenesis (Corti et al. 2003).


MAPT is the Microtubule Asssociated Protein Tau gene which is found on chromosome 17 at the 17q21.1 location which is responsible for the formation of the protein Tau (Abel et al. 1993, Andreadis et al. 1992). Tau is a protein with 6 different isoforms (a result of mRNA splicing) that is responsible for the assembly and stability of microtubules and is therefore directly implicated in the maintenance of the cytoskeleton of the cell and overall cell transport (Nagase et al. 1999, Alonso et al. 1996).

Depending on the type of isoform of the tau protein, typical length can vary between 352 to 441 amino acids (Goedert et al. 1989). The proteins contain region on the C terminal called a microtubule binding domain which is involved in the interaction of the protein with the microtubule network. This region varies depending on the isoform; half of the isoforms have a binding domain that consists of 3 repeated segments whereas the other half has a binding region that has a 4 repeat segment (Hutton et al. 1998). Both the 3 repeat and 4 repeat isoforms have core binding domains that lead to intramolecular folding interactions and therefore different functional properties (Goode et al. 2000).

The tau protein is predominantly found in neurons in the brain where it interacts it with the microtubules found in the distal part of the axons in nerve cells. Therefore mutations in the MAPT gene or alteration of the function of the tau protein can often lead to neurological disorders such as PD and AD. Neurofibrillary tangles (NFTs) and senile plaques are two lesions that are very typical to AD that are associated with the tau protein; senile plaques are deposits of fibrillar beta amyloid peptides that are a result of tau pathology and NFTs are hyperphosphorylated bundles of tau proteins (Rapoport et al. 2002).

NFTs are made up of paired helical filaments (PHFs) which are themselves made up of hyperphosphorylated tau known as "AD P-tau". In its phosphorylated form tau is unable to interact with microtubules (thus disrupting the cytoskeletal structure of neurones) and it associates with normal tau to form NFTs. Normal tau proteins have around 30 Serine and Threonine (Ser/Thr) phosphorylation sites (out of a potential 79) which are phosphorylated by a variety of kinases. Formation of NFTs in the brain can be attributed to three families of Ser/Thr kinases; GSK3 kinases (both alpha and beta forms), MAPK (p42,p44 and ERK/p40) and CDC2 kinases (such as cdk5). All three kinase families are involved in the phosophorylation of tau, however some are more involved in the formation of NFT and AD like pathology than others (Billingsley & Kincaid, 1997).

MAPK is often found in neurones with PHFs and therefore overexpression of this kinase may potentially result in increased phosphorylation of tau proteins. MAPK itself is activated via phosphorylation by other kinases such as cdk5. ERK2, p44, p42 and p49 are all MAP kinases that are localized to brain tissue and when overexpressed are involved in the phosphorylation of tau. This selective phosphorylation has been shown to occur on Ser202, Ser422 and Thr205 of the tau protein (Lambourne et al. 2005). MAPK signalling is controlled by CDC kinases, a family of kinases that have members such as cdk5 implicated in playing a role in the hyperphosphorylation of tau protein (Chen & Thorner 2007).

GSK3 kinases can potentially cause tau phosophorylation and disrupt tau-microtubule interactions. GSK3 has two isoforms that are heavily involved in cell signalling; GSK3-alpha and GSK3-beta are proline directed Ser/Thr Kinases that are involved in gene transcription, glycogen metabolism, cell apoptosis and microtubule formation (Hooper et al. 2008). They are responsible for the hyper-phosphorylation of tau proteins at Thr231 and the subsequent neurodegeneration due to NFT formation which results in AD. Furthermore, inhibiting the GSK3 in mouse models using lithium prevents the tau hyper-phosphorylation but does not reverse NFTs that are already formed (Engel et al. 2006). Further observations include the localization of GSK3 with NFTs and the up-regulation of GSK3 activity in the frontal cortex and the hippocampus in AD patients (Blalock et al. 2004, Leeroy et al. 2007). It is worth noting that the increased activity of GSK3 is suggested indirectly, as the use of post mortem tissue results in difficulty when trying to directly analyse enzymatic activity (Hooper et al. 2008).

The CDC2 like protein kinase CDK5 (or tau kinase II) is highly enriched in neurones, localized to microtubules and involved in neuronal development, brain development and the general development of the human CNS. In order to carry out phosphorylation it must first be activated by its regulatory neuronal activators p35 and p39 and these activators are highly expressed in the brain, where phosphorylation of tau can lead to development of NFTs and AD. In animal models the expression of p39 occurred in the brain stem and cerebellum whereas the expression of p35 primarily occurred in the cerebral cortex. The same studies also showed that the cdk5/p39 complex preferentially phosphorylates tau when compared to the cdk5/p35 complex (Takahashi et al. 2003). Phosphorylation of the tau protein by cdk5 primarily occurs at Thr205 and Thr231 as well Ser195, Ser202, Ser235, Ser396 and Ser404 on tau, a process made possible due to cdk5 localizing at the cytoskeleton where tau interacts with the microtubule network (Billingsley et al. 1997). Studies have shown that inhibition of cdk5 with a highly specific inhibitor results in no cdk5 mediated phosphorylation of tau protein and therefore no neurodegeneration via apoptosis, further supporting the evidence for the role of cdk5-tau interactions in AD (Zheng et al. 2004). The p25 regulatory subunit is an altered version of the p35 subunit caused by calcium dependent protease called calpain, whose inhibition prevents the formation of this subunit (Lee et al. 2000). Expression of p25 results in dysfunctional regulation of cdk5 upon binding to it; when p25 accumulates in the brain, the cdk5 mediated hyperphosphorylation of tau protein increases and the activation is constitutive as the p25 subunit is much more resistant to degradation compared to p35 (Patrick et al. 1999). Although not related to its role as a kinase to tau, studies have shown that cdk5 is both a potential regulator of apoptosis in DA neurones, a key feature of PD, and an indirect inhibitor of PKA which is one of the kinases involved in the phosphorylation of tau protein. Both these interactions may have implications on the progression of neurodegenerative disease (Bibb et al. 1999, Smith et al. 2003).


The APOE gene is 3597 bp in length and is located on chromosome 19 at the cytogenetic location 19q13.32 that is involved in late onset Alzheimer’s Disease. There are three major isoforms of APOE; apoe2, apoe3 and epoe4 with the difference between the three isoforms being changes in amino acids at position 112 (referred to as site A) and at position 158 (referred to as site B). In apoe2 the configuration of site A/B is cysteine/cysteine, in apoe3 the configuration is cysteine/arginine and in apoe4 the configuration is arginine/arginine (Rall et al. 1982). The three isoforms differ in structure, function and allele frequencies; apoe2 is the least naturally occurring isoform at 7% frequency, apoe3 is the most commonly occurring wild type isoform at 79% frequency whereas apoe4 is in the middle with 14% frequency and is of particular relevance to us as it is involved in neurodegeneration, degeneration of cognitive abilities and AD pathology (Saunders et al. 1993).

The gene for late onset AD is mapped to the same region of chromosome 19 as the APOE gene in patients with late onset AD and a correlation was found between the increasing numbers of E4 alleles and an increased susceptibility for AD in ageing patients (Corder et al. 1993). Additionally E4/E4 homozygotes were shown to cause a much earlier onset of AD than E4/E3 heterozygotes (Borguankar et al. 1993) however there have been exceptions to this where apoe4 is not linked with development of AD (Hyman et al. 1996) or where there is no early onset of the disease as a result of apoe genes (Levy-Lahad et al. 1995). Both NFTs and senile plaques are associated with AD pathology and contain Apoe proteins; both apoe3 and apoe4 isoforms bind to amyloid beta peptides, although the binding time of apoe4 is much quicker than the binding time for apoe3 resulting in a possible link being implied between apoe binding/oxidation and the development of AD pathology.

Apoe shows interactions with the MAPT protein which has been shown to be involved in the formation of NFT, amyloid plaques and the formation of microtubules. The type of interaction depends on the type of isoforms of apoe involved in the binding with MAPT and it possible that the two work together to result in AD development (Strittmatter et al. 1995).


GBA is a gene 515 amino acids in length found on position 1q22 on chromosome 1 that codes for the enzyme beta-glucosidase. GBA is an enzyme located in lysosomes that are involved in the hydrolysation of glucocerebrosidase, which plays a role in the metabolic processes inside the cell, into glucose and ceramide. Since GBA plays an important role in metabolic regulation in cells, alterations in its functions causes disorders such as Gaucher’s disease and PD (Beutler et al. 1992). There are various mutations that are related to PD and DLB and various studies have highlighted the associations of the L444P and N370S mutations in particular and have established them as genetic risk factors for patients (Ahron-Pheretz et al. 2004, Goker-Alpan et al. 2006, Tan et al. 2007, Gutti et al. 2008, Mata et al. 2008). Full gene sequencing of patients with PD has shown that there is no direct mechanism of inheritance that links GBA mutations with PD, however GBA itself increases overall susceptibility of an individual to develop PD symptoms much earlier when compared to patients without the GBA mutations. It has also been shown that having the mutation results in increased likelihood of relatives also being susceptible to the disease (Sidransky et al. 2009).

One of the major GBA mutations associated with DLB and PD is the exon 10 leucine444 to proline substitution that is heterozygous, as opposed to homozygous mutations that are generally associated with Gauchers Disease (Zimran et al. 1989, Widgerson et al. 1989). The N730S mutation is a asn-to-ser substitution that takes place on exon 9 and is very often associated with Gauchers Disease in Ashkenazi populations (Tsuji et al. 1988). However heterozygous mutations have been implicated in increased susceptibility to PD and DLB in patients of European descent, although it the risk only occurred in three percent of the patients in the actual study (Mata et al. 2008). An arginine-to-cystine substitution known as R463C is also related to Gaucher Disease and a heterozygous mutation results in an increased susceptibility to late onset PD (Neumann et al. 2009). Finally, the D443N mutation is an asp-to-asn substitution that has been associated with an increased susceptibility to late onset parkison’s disease and unlike N730S and R463C it has not been associated with Gauchers Diseases and is therefore a mutation exclusively linked to PD (Neumann et al. 2009).

GBA has shown interesting interaction with SNCA which is responsible for the synucleopathies that are present in DLB, PD and Lewy bodies. Mutations in GBA result in the formation of dysfunctional beta-glucosidase enzyme which means that proteins such as SNCA are unable to undergo lysosomal hydrolization. The increased levels of alpha-synuclein serve to further impair the beta-glucosidase activity in the brain as well as potentially increasing lewy body formation. This effectively results in a positive feedback mechanism that may be a major cause of lewy body formation in DLB and PD (Mazulli et al. 2011).


The APP gene is also known as the amyloid beta precursor protein and is found on cytogenic location 21q21; it spans around 175kb, has 19 exons and is expressed in the CNS and brain (Yoshikai et al. 1990). It codes for the beta-amyloid precursor protein which then undergoes post-translational processing to result in the formation of the beta-amyloid protein that is associated with AD and the formation of senile plaques. When APP is proteolytically cleaved by alpha secretase it creates the 4.2kD beta-amyloid protein which is soluble and has a semi-beta pleated sheet structure (Masters et al. 1985, Esch et al. 1990, Senvik et al. 2000). There is also proteolytic cleavage possible with gamma secretase and beta secretase (Grimm et al. 2005).

APP is also implicated in the transport of iron which is due to its similarity to feroxidase enzymes that are able reduce the levels of iron when localized in the cortex. The oxidative stress which is a result of iron accumulation may leads to the formation of beta-amyloid plaques that are typical of AD (Duce et al. 2010).

As wildtype APP protein undergoes extensive post-translation processing it is important to review the general interactions between APP and its associated proteolytic enzymes such as BACE1, gamma-secretase, PSEN1, caspase, PIN1 and 5-CO.

BACE1 is a beta-secretase localized to axons/axon terminals which extracellularly cleaves APP to eventually form beta-amyloid. BACE1 cannot produce beta-amyloid on its own, it initiates the process and the product of the BACE1-APP cleavage is then further cleaved by gamma-secretase to form beta-amyloid 40 and 42 as well as a fragment known as AICD (Vasser et al. 1999, Yan et al. 1999, Grimm et al. 2005). Overexpression of BACE1 predictably leads to increased production of beta-amyloid due to higher rates of APP cleavage. Peculiarly, it was found that with exceptionally high expression of BACE1 results in a reduction of beta-amyloid produced. This is due to BACE1 relocating its expression to the soma of the neurone thus interfering in the transport of APP (Lee et al. 2005). Regulation of the expression and stability of BACE1 is done by BACE1-AS; the amount of BACE1-AS expressed increases as the level of beta-amyloid 42 increases which results due to overall increase in the BACE1 stablilty which is in fact a positive feedback mechanism. Since it was shown that knocking out BACE1-AS in animal models resulted in decreased levels of beta-amyloid it is suggested that BACE1-AS may play an important role in Alzheimers disease due to its regulation of BACE-1/beta-amyloid (Faghihi et al. 2008).

Gamma-secretase, much like alpha and beta secretase, is a protease involved in the cleavage of APP to form beta-amyloid. As mentioned before, APP is first processed by BACE1 and the product of this is then cleaved by gamma-secretase. In order for the gamma-secretase to be functional it must form a complex with Prensilin Enchancer 2 (PEN2) and ADPH1 and without the presence of these proteins the stability of the gamma-secretase would decrease resulting in decreased rate of formation of beta-amyloid from APP (Takasugi et al. 2007). PSEN1 also takes part in this process and interacts with the gamma-secretase; in studies performed on animals PSEN1/2 mutations resulted in an increase in the formation of the cleavage product beta-amyloid and therefore increase the likelihood of the formation of amyloid plaques (Citron et al. 1997). The AICD fragment produced by the cleavage of APP results in an overall decrease in beta-amyloid levels due to it being degraded (Pardossi et al. 2005). Gamma-secretase mediated cleavage of beta-amyloid is altered by mutations in certain motifs (GxxxG) which results in the beta-amyloid being cleaved at positions that are different to the positions that it is normally cleaved at. This results in an overall decrease in the rate of beta-amyloid production and therefore this is a potential therapeutic pathway in the treatment of AD (Takasugi et al. 2003). In fact even mutations near its site of cleavage can result in a failure to produce the normal fragments of beta-amyloid, instead resulting in dysfunctional fragments (De Jonghe et al. 2001).

There are various mutations of wild type APP that result in the formation of beta-amyloid plaques and general AD pathology. These mutations are most commonly Val, Lys, Ala, Glu, Thr and Ile substitutions.

The Val717ILE mutation in APP is a result of a Cytosine2149 to Thymine transition in the APP gene which results in a novel restriction site which disrupts the associations between APP and Apoe4, as well as altering the cleaving of APP by gamma-secretase. This results in an alteration in the amount of amyloid-beta 40 and 41 expressed, which in turn results in the formation of pathological features associated with AD (Maruyama et al. 1996).

Another mutation of the APP gene is a Guanine to Adenine transition which results in a Val715 to Met substitution in the APP protein which is implicated in early onset AD; as a result of the mutation there was an increase in the amount of a beta-amyloid 42 isoform, and this may be associated with AD (Maruyama et al 1996).

A Guanine to Thymine transversion in APP results in a val717 to phe substitution in the APP protein. Overexpression of this protein also resulted in the development of amyloid plaques and AD pathology, as well as giving important insights to the role of APOE in the regulation of beta-amyloid aggregates (DeMattos et al. 2004).

The Ala692Gly mutation of APP is a result of of a cytosine to guanine transversion which not only results in AD pathology but is also implicated in the development of cerebral amyloid angiopathy. The mutation resulted in an increase in production of beta-amyloid 40/42 which is linked to development of AD pathological features (De Jonghe et al. 1998).

On the APP gene an Adenine to Cytosine/ Guanine to Thymine transition at position 717 results in a lys670/671 to asn substitution which results in the formation of altered sites of cleaving which can result in increased expressions of the beta-amyloid protein in patients with AD. This increase was due to the cessation of the separation of alpha-secretase and beta-secretase via compartmentalisation resulting in an increase in the competitive cleavage of APP. This double mutation is also known as the Swedish mutation (Mullan et al. 1992, Haass et al. 1995). Animal models with this mutation showed cognitive difficulties with increasing age, the formation of amyloid plaques in the brain that would interact with tau protein, dysfunctional regulation of APP leading to neurodegeneration and general AD pathology (Hsiao et al. 1996, Calhoun et al. 1998).

An Adenine to Guanine transition results in the E693G substitution which is associated with AD as well as cerebral amyloid angiopathy. This mutation would result in a marked increase in the formation of beta-amyloid plaques and NFTs resulting in an overall decreased of the beta-amyloid isoforms present in the plasma (Kamino et al. 1992, Nilsberth et al. 2001). Like other mutations, this one showed the typical hallmarks of AD such as neurodegeneration, decline in cognitive abilities and formation of NFTs, however in this case symptoms of cerebral amyloid angiopathy were also present (Basun et al. 2008).

In the APP gene a Cytosine 2208 to Thymine transition results in a formation of a Thr to Ile substitution at position 714, and this mutation is primarily associated with an imbalance of the levels of the two isoforms of beta-amyloid that are produced via cleavage by gamma-secretase. This leads to the development of AD as increased amounts of beta-amyloid 42 to have been linked to the pathological features of AD (Kumar Singh et al. 2000).

Duplication in the APP gene has been linked with both AD and Cerebral Amyloid Angiopathy (Rovelet-Lecrux et al. 2006). Most patients with mutation display the symptoms of both AD and cerebral amyloid angiopathy, and AD onset occurs relatively early and is autosomal dominant (Guyant-Marechal et al. 2008).

Unlike most of the other mutation the Ala673 to Thr mutation is protective against AD due to an overall reduction in the numbers of beta-amyloid isomers produced via alteration of alpha-secretase and beta-secretase cleavage (Jonsson et al. 2012).


PSEN1 is a 47 kD gene consisting of 13 exons that is found on chromosome location 14q24 that codes for the Presenilin1 protein which is involved in the processing of various proteins, one of which is the Amyloid Protein Precursor which is associated with AD development (Kovacs et al. 1996, Li et al. 1997).

Wild type Presenilin 1 is usually expressed in the neurones of the hippocampus and human cortex (Page et al. 1996). The protein is localized to the Endorplasmic reticulum of neurones via a C terminal signal peptide (Kaether et al. 2004). Presenilin 1 is involved in the production of amyloid-beta from the APP protein via interactions with gamma-secretase. In order to cleave APP, gamma-secretase must form a complex with various proteins (see; APP section of review) one of which is presenilin 1 in order for the hydrolyzation/cleavage to occur (Li et al. 2000, Kopan and Goate 2000). Thus the stability of the gamma-secretase complex involved in the production of beta-amyloid from APP is associated with Presenilin 1 activity.

A glu280-to-ala mutation in the prenesilin 1 protein is associated with AD as it alters the ratios of amyloid-beta isomers present in the plasma. The prenesilin 1 protein mutation changes the gamma-secretase mediated cleavage of APP which leads in an increase of beta-amyloid 42 which is strongly associated with the formation of NFTs and amyloid plaques that are typical of AD pathology (Lemere et al. 1996).

There is a met146-to-leu substitution mutation in the Prenesilin 1 protein which is a result of an Adenine to Thymine transversion in the PSEN1 gene (Morelli et al. 1998). This mutation does not appear to affect the function of gamma-secretase but it does affect the hyperphosphoryation of tau which ultimately results in the formation of NFTs that are typical of AD (Halliday et al. 2005).

A PSEN1 mutation involving a guanine to thymine transition results in a deletion mutation which causes the disruption of the post-translational processing of the presenilin 1 protein; this would indirectly affect the ability of the presenilin 1 protein to form a complex with gamma-secretase (Perez-Tur et al. 1995, Thinakaran et al. 1996). The alteration of the PSEN1 gene results in a deletion of exon 9 which results in the formation of NFTs and amyloid plaques due to the alteration of the levels of the beta-amyloid isomers produced (Crook et al. 1998).

Another deletion mutation that occurs is a result of a Guanine deletion in the PSEN1 gene which results in an increase in the production of beta-amyloid 42 isomer which is strongly associated with AD (De Jonghe et al. 1999).


The SORL1 gene is found on cytogenic location 11q24.1 which functions as a receptor for the APOE protein. In terms of structure it it is similar to LDL Receptors and Vps10 receptors, has a site for the cleavage of furin, a secretory sequence, various domain repeats, and a TM domain, and is expressed primarily in the human CNS where it is involved in endocytosis (Jacobsen et al. 1996, Jacobsen et al. 2001). Initially it was recognized as a receptor with sortilin domain that was able to bind RAP, otherwise known as the Receptor Associated Protein which is a class of molecular chaperone proteins (Korenberg et al. 1994) however it can also bind to LDLR through functional domains located in the domain repeats (Jacobsen et al. 2001).

In patients with AD there was a pronounced reduction in expression of SORL1 in the pyramidal neurones of the frontal cortex and this reduction of expression appears to correlate with AD progression. This association is particularly relevant considering the fact that APOE is linked to AD and that SORL1 is an APOE receptor (Scherzer et al. 2004, Sager et al. 2007).

SORL1 is also a key component in the targeting of APP to be recycled via endocytosis which means that any alteration in the expression of the receptor would result in the APP being converted into amyloid beta peptide instead which results in the formation of amyloid plaques that are typical to AD (Rogaeva et al. 2007). Additionally various studies have found various alleles of SORL1 to be associated with an increased overall susceptibility to AD (Reitz et al. 2011).


SNCB is a gene that is found on the cytogenic location 5q35 coding for the 134aa beta synuclein protein which is primarily localized to presynaptic terminal of neurones in the human brain (Spillanti et al. 1995). Unlike the very similar alpha synuclein, the expression of wild type beta synuclein was not associated with PD, DLB or lewy body formation in general (Spillanti et al. 1997). Instead the expression of beta synuclein appeared to have a protective effect against the neurodegenerative effects of alpha synuclein aggregation and subsequent formation of inclusions. It is possible that the regulatory effect of beta synuclein on alpha synuclein may be a result of the former’s interaction with Akt signalling (Hashimoto et al. 2001, Hashimoto et al. 2004).

Two mutations of SNCB have been related to the formation of lewy body dementia in patients most likely to the loss of function of the beta synuclein and loss of ability to downregulate the accumulation of alpha synuclein aggregates.

The V70M mutation of SNCB occurs when a Guanine208 to Adenine transition in SNCB leads to a val70-to-met substitution in the beta synuclein protein. This changes the proteins teritiary structure resulting in a dysfunctional beta synuclein protein which allows an increase in alpha synuclein aggregation that leads to lewy body formation in DLB (Ohtake et al. 2004).

The P123H mutation of SNCB occurs when a Cytosine368 to Adenine transversion occurs in SNCB leading to a pro123-to-his substitution in the beta synuclein protein. Like the V70M mutation this results in the formation of a dysfunctional beta synuclein which results in increased aggregation of alpha synuclein in the substantia nigra and hippocampus and subsequent lewy body formation typical to DLB (Ohtake et al. 2004).