Despite the fact that Alzheimer’s (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases, their pathogenesis still remains largely not well understood. However, advances during the last few decades in the characterizations of rare mendelian mutations and common risk genes as well as the role of epigenetics have greatly enhanced our understanding for the role of heritability and environmental factors in the development of AD and PD. This paper reviews key findings along their molecular mechanisms while tries to provide an overview of the overall contribution of genetics and epigenetics in the two diseases. Moreover, recent findings on neuronal genetic instability are also mentioned and, finally, a model that tries to integrate the effects of genetics, epigenetics, environment and pathological processes is proposed supporting the hypothesis that few ‘seeding’ pathogenic foci are sufficient to produce generalized pathology.

Introduction and Insight from Twin Studies. 

Alzheimer’s (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases affecting about 1% and 0.5-1% in 65-69 years old and up to 50% and 4% respectively in older groups.[1-3] The pathogenesis of the two diseases is heterogeneous and not well understood although the long-standing involvement of specific protein misfolding and aggregation is well characterised in each case. AD presents as an insidious and progressive deterioration of global cognitive functions and is histopathologically recognized by the accumulation of extracellular amyloid-β-containing (Aβ) plaques and intraneuronal deposits of hyperphosphorylated τ protein (pτ) in the form of neurofibrillary tangles (NFTs). Both soluble/prefibrillar and fibrillar Aβ together with pτ are highly implicated in axonal transport failure, deranged dendritic signalling, excitotoxicity and ultimately cell death.[4,5] Similarly, in PD, which predominantly but not solely affects the dopaminergic system leading to a wide range of motor and neuropsychiatric symptoms, α-synuclein-containing intraneuronal Lewis bodies (LBs) are considered hallmark of the disease,[6,7] while the role of deranged protein handling, ubiquitin proteasome system (UPS) and mitochondrial dysfunction, and increased oxidative stress are considered to be pivotal.[8,9] 

Nonetheless, even if age and environment are important factors, the role of genetics has been and is still extensively investigated. The recognition of rare family clusters of early-onset AD and PD cases versus the common late-onset sporadic cases has led to a ‘genetic-dichotomy model’ according to which EOAD is associated with fully penetrant rare mutations while LOAD with common genetic polymorphisms that modify the susceptibility risk of individuals.[10,11] However, an appreciation of their overall contribution in the two diseases can be better achieved by looking into twin studies. Such studies in AD have indicated that genetics contribute 48-60% in it’s development.[12-14] On the other hand, cross sectional PD studies have surprisingly revealed very low concordance rates in monozygotic twins and overall heritability[15,16] and only a longitudinal study gave a heritability estimate of 40%[17] denoting the importance of environment and variability in disease onset. However, this does not exclude important genetic contributions, as genetic polymorphisms with low penetrance and gene-environment interactions can still be widely implicated.[18] Evermore, current lines of thought suggest that plastic and rigid epigenetic differences could actually account for environmental or even inherited factors.[19-21] Therefore, aim of this essay is to investigate the aetiological roles of genetics and epigenetics in AD and PD. 

Genetic factors in AD

Both the amyloid cascade and other derived hypotheses underline the central role of Aβ in AD pathogenesis.[4,5] Aβ is a 38-43 residue peptide physiologically produced by the sequential action of β- and γ-secretases on the Amyloid Precursor Protein (APP);[22] and 85% of familial EOAD cases seem to be caused by autosomal dominant mutations in the genes encoding APP and presenilins 1 and 2, which contribute to the γ-secretase complex.[23] It is generally accepted that these mutations increase the levels of pro-fibrilar/toxic Αβ peptides (Figure 1) although upregulation of inflammatory pathways could be still implicated.[24] 

Figure 1. Mendelian mutations and risk polymorphisms directly linked to the amyloidogenic pathway. The amyloid precursor protein (APP) can be processed in two ways. In the non-amyloidogenic patway APP is cleaved by α-secretases at a cleavage site within the Aβ sequence (purple) producing so non-plaque-forming peptides with possibly neuroprotective effects. In the amyloidogenic pathway, APP is first cleaved by β-secretase and then by the γ-secretase complex which is formed by presinilins (PSEN) 1 and 2, nicastrin and either anterior pharynx 1 A or B. γ-Secretase first cleaves at a site close to the intracellular domain and then continues to trim the residual intramembrane fragments producing the Aβ peptide whose length can vary, although at physiological conditions Aβ40 predominates. The effect of different mendelian/fully penetrant mutations and that of a protective APP polymorphism is shown in the diagram. Effectively pathogenenic genotypes can i) increase APP expression and hence Aβ synthesis, ii) promote the amyloidogenic pathway and overall Aβ synthesis or iii) promote pathogenic Aβ profiles. Based on [25-28]. Interestingly, gene knockdown strategies employing siRNA seem to have some positive effect. Targeting presinilin 1, downregulates Aβ42 in vitro[116] and conditional inactivation in mice can actually temporarily rescue cognitive impairment.[117] On the other hand, targeting APP can produce adverse phenotypes and cognitive problems in mice.[118] 

Moreover, potentially loss-of- function mutations in the SORL1 gene were lately found in 5 unexplained autosomal dominant EOAD cases although incomplete penetrance was not excluded.[29] SORL1 promotes neuronal APP recycling and actually expression of SORL1 is shown to be inversely related with Aβ synthesis.[30] Additionally, unexplained familial EOAD cases have also been found to be associated with genetic copy number variations (CNVs) such as duplications of the APP locus.[31,32] See Figure 1. Interestingly, trisomy 21, which involves the APP gene, is known to lead to AD pathological changes by middle age[35] and the only person with Down’s known to have escaped AD, had only two copies of APP.[36] Evermore, CNVs affecting other genes possibly related with AD pathology have also been recently associated with EOAD[33,34] (see Table 1) and even if extremely rare and not yet proved causal, their further investigation is important for understanding AD pathogenesis and possible therapeutic targets.

However, although some fully penetrant mutations can explain some LOAD cases, overall they still account for less than 1% of all cases.[37,38] Hence the role of common low-penetrant polymorphisms must be more significant. The gene most consistently identified with risk factor genotypes is APOE, which has three isoforms (ε2-4) and normally promotes Aβ degredation.[39] It is commonly reported that ε4 homozygocity confers a 15-fold increase in risk and up to 20 years earlier disease onset, while ε2 is protective.[41-44] However, most studies are cross-sectional and a recent longitudinal study showed that ε4 carriers despite being more likely to develop mild cognitive impairment, the transition-likelihood to AD is not different,[45] suggesting that ε4 may not actually affect life-time risk but just decrease age of onset, as is the case in familial AD.[46] See also[47,48]. Additionally, very young ε4 carriers seem to have (developmentally?) decreased entorhinal cortex volumes,[49] limiting perhaps the ‘threshold’ for manifesting the disease in susceptible individuals (see Figure 2). The second most important determinant is a locus upstream of BIN1,[50-52] which modulates BIN1 expression and BIN1-related τ-mediated neurotoxicity.[53] SORL1 polymorphisms affecting its expression are also associated with increased AD risk.[30,54-57] Many other genetic polymorphisms have been associated with increased AD risk (see [58]) although their quantitative impact and mode of contribution may need further investigations as shown by the case of APOE.Alzheimer’s and Parkinson’s diseases are two complex and very heterogeneous diseases with regards their underlying genetic aetiology, onset and pathology. The existence of rare fully penetrant mutations sufficient to cause each disease and that of common genetic polymorphisms conferring increased risk or modulating other aspects of the disease, have revealed many key molecular pathways and processes that are involved – to different extents – in the manifestation of both AD and PD. Even though, the quantitative contribution of each factor may not be clear, future approaches analyzing genetic variations within the context of molecular pathways, measurable biomarkers, epistatic and environmental interactions, genomic instability and mosaicism, may lead to a better characterization of the role that genetics play in the aetiology of PD and AD. However, the picture would be incomplete without integrating the findings from epigenetics. As summarized in Figure 4, it is probably the interplay between all these that ultimately determines the disease outcome, and evermore, the appreciation of the contribution of possibly multiple pathologic loops in AD and PD pathogenesis may inform future multiple target therapies.

Finally, a new paradigm shift has occurred with the realisation that up to 40% of human neurons have CNVs[59] while 10% are aneuploid and that actually neuronal DNA replication and increased aneuploidy states (e.g. 10-fold increase of chromosome 21-specific aneuploidy) precede neuronal death in AD.[60-62] What is more, Suberbielle et al. showed recently that neuronal activity is normally associated with double-strand breaks (DSBs) in neurons of young adult mice and that transgenic mice models expressing human APP not only had increased neuronal DSBs at baseline but Αβ further amplified and prolonged DSBs related to increases in neuronal activity. The ultimate consequence of this increase in DSBs in AD is not yet known but could contribute in cell deregulation and death. All these definitely paint a very complex and incomplete picture of AD genetics and furthermore emphasize the possibility that a two-way process, in addition to interactions between hundreds or thousands of different inherited and acquired polymorphisms within certain cell populations, determines the disease outcome. 

Genetic factors in PD

Similar to AD, the central role of α–synuclein in PD was further recognized when uncommon mutations and CNVs (duplications/triplications) of the SNCA gene were found to cause autosomal dominant PD in both familial and sporadic cases, showing that altered function and increased expression are sufficient to cause PD.[63-68] Interestingly, PD with dementia is more common with SNCA duplications and early onset aggressive PD or dementia with LBs more common with triplications[65] revealing that the PD phenotypes may be actually a part of a clinicopathological continuum with not distinct boundaries. Nonetheless, the most commonly affected gene, accounting for 6% of familial and 2% of sporadic cases (depending on ethnicity) is LRRK2.[69] Its function is not well understood but it seems to interact with α-synuclein, affect LB formation[70] and misregulate autophagy,[71] explaining perhaps the great pathohistological heterogeneity of pτ aggregations or LB absence in some carriers.[69] Rare gene mutations causing autosomal recessive forms have also been found and seem to be associated with mitochondrial dysfunction and increased oxidative stress (DJ1, PINK1, parkin); or disregulation of the ubiquitin-proteosome system (parkin and UCHL1).[65] See Figure 3. Finally, there are several mutations that either cause very atypical PD or other pathologies too (e.g. ATP13A2, ATXN2, ATXN3, FBXO7)[72] raising questions about current PD classifications. 

Although mendelian mutations could explain a few sporadic cases, common low-risk polymorphisms are also implicated in PD as in AD. Not surprisingly, locus variability of the SNCA promoter,[73] or SNCA itself,[74,75] which correlates with altered α-synuclein expression,[76,77] is associated with increased risk; accounting for 3% and 12% of cases (>10% α-synyclein expression translates in 40% increase in risk).

Furthermore, variability of the microtubule-associated protein tau (MAPT ) gene, could also contribute towards 8% of cases,[74] even though mendelian mutations do not cause PD but other neurodegenerative diseases. Interestingly, common HLA variations also seem to be strongly implicated (underlining the role of neuroinflammation),[79] but while variation in the HLA region several other genes have been proposed, they do not have as strong associations.[71] Finally, on another note, it has been suggested by in silico analysis that somatic transpositions, which are common in the brain, have the potential to alter biosynthesis of metabolites involved in PD, but further research is needed to characterise their role in PD pathogenesis.[80]

The role of the mother

One of the most interesting recent findings is that Αβ burden is higher in people with maternal history of AD than those with paternal or none,[81] and actually normal individuals with maternal history also exhibit more atrophic changes.[82] One possible explanation is that AD risk is associated with mitochondrial-DNA (mtDNA; always inherited maternally) and supporting this, normal individuals with maternal history have increased markers of oxidative stress[83] and certain mitochondrial haplotypes are also associated with AD biomarkers.[84] Similarly, the role of mitochondria in PD has already been stressed, and a study in a family with strong maternal inheritance profile, showed that maternal descendants had more abnormal mitochondrial morphologic features and increased reactive oxygen species as shown in vitro by cell lines expressing donor mtDNA.[85] Additionally, several studies have shown the existence of protective and risk mtDNA haplogroups[86-89] emphasizing the role of mitochondrial dysfunction and oxidative stress in PD pathogenesis. An alternative explanation could be parental epigenetic imprinting of pathogenic genes but there is no current evidence. 

The Heritability Gap

Despite the abovementioned evidence, there is still a big gap from what would be expected and by regarding AD and PD as complex and largely heterogeneous diseases one can postulate that the effect of rare and structural variants and gene-gene (epistasis) or gene-environment interactions is “beyond the reach of the conventional single-variant association testing procedures”[90] which most-times consider clinical diagnosis as outcome against single variations even though it is known that histopathology and hence the contribution of different pathological pathways varies between individuals. Therefore it could be argued that future analyses should focus more on ‘network-centric approaches’ that consider gene-gene interactions, molecular pathways[90,91] and disease-biomarkers as outcomes too. 

The Role of Epigenetics

The epigenome refers to all mechanisms of “mitotically or meiotically heritable changes in gene expression that do not involve alterations in the DNA sequence”[21] such as methylation, histone modification and regulatory RNA. Such changes can be inherited, erased or modified and can be cell-specific. Generally three types of epigenetic variation are recognize as the epigenotype is strictly determined or just facilitated by the genotype, or is genotype-independent/stochastic.[20] Hence, while monozygotic twins are epigenetically identical early in life, by age 50 a 30-35% concordance drift occurs with respect to methylation and histone modification.[92] Consequently, epigenetics integrate the contribution of both inherited and environmental factors and epigenetic regulation or deregulation could determine the outcome of complex diseases, especially when age is a major risk factor as in PD and AD. 

With regards to AD, it has been shown that normal ageing is correlated with demethylation of the APP promoter probably underlying increased Αβ deposition in the ageing brain.[93] Evermore, very recently Iwata et al.[94] revealed aberrant CpG methylation within the APP and MAPT genes in the AD brain, which in vitro resulted in increased protein expression. In particular, they calculated that the temporal cortex hosted 2-5% of very abnormally methylated cells, which – by considering the prion-like behavior of Αβ and τ–[95] could then serve as “seed clones for aggregated protein production.”[94] Generally, previous studies have shown that AD is associated with abnormal methylation patterns[96] and reduced epigenetic markers and regulators,[97] suggesting that AD is associated with epigenetic deregulation. Interestingly, it was found that methylation levels of MTHFR, involved in methylation homeostasis, and APOE decreased in ageing controls whereas they increased in AD brains.[96] One genome-wide DNA methylation study identified about 1000 possible risk sites.[98] Furthermore, AD is associated with altered miRNA levels which could up-regulate APP and beta-secretase.[99,100]

These epigenetic differences could be explained either as the result of inheritance and environmental factors or as part of AD pathogenesis. Supporting the former, neonatal but not adult Pb-exposure of rats results in increased APP and Αβ expression in old age,[101] while folate deficiency (which affects methylation homeostasis) is associated with PSEN1 over-expression in ε3 and ε4 (but not ε2) transgenic mice, while folate-deficient ε4-mice exhibit increased Αβ synthesis as well.[102] Additionally, diabetic brains show increased expression of certain histone deacetylases (HDACs), and diabetic mice show increased HDAC-mediated susceptibility to Aβ-induced synaptic impairments, explaining diabetes as AD risk factor.[103] On the other hand, Aβ addition in endothelial cells seems to induce global DNA hypomethylation and further suppress neprilysin, which facilitates Aβ degradation. 

Similarly, samples from sporadic parkinsonian brains show reduced methylation in SNCA intron 1 compared to controls, and it has been shown that such hypomethylation increases α-synuclein expression.[104] Moreover, there is some evidence that α-synuclein induces global DNA hypomethylation (involving SNCA too) by sequestering DNA methyltransferase 1 (involved in DNA methylation)[105] and furthermore was shown to have toxic effects by binding directly to histones preventing their acetylation.[106] Interestingly, methylation markers correlate with both APP and α-synuclein and increased methylation potential is associated with better cognitive status in PD patients.[107] However, at the same time α-sunuclein-mediated acetylation inhibition actually down-regulates specific apoptotic pathways conferring so a neuroprotective effect.[108] Hence potential therapeutic targets should be very specific. Nevertheless, well-characterized toxins causing parkinsonism (paraquat, rotenone, dieldrin) and even L-Dopa also modulate histone acetylation.[109, 110] 

Finally, sex hormone imprinting could account for the differential susceptibility of males and females (AD is more common in women,[1] while PD in men[111]). For instance, it has been shown in mice PD models that the neonatal exposure to endogenous sex hormones determines not only adult susceptibility of neurons but also whether estrogen could have a protective or detrimental effect.[112] Such sexual dimorphisms possibly at the epigenetic level could also explain the possibility that certain genetic polymorphisms (e.g. in SORL1) confer a female-specific increased risk for AD.[113, 114] 

It is evident that epigenetic imprinting and deregulation due to environmental factors cannot only increase Αβ and α-synuclein expression in susceptible cells, but the latter can further deregulate the epigenome in in AD and PD and further propagate the pathology via prion-like mechanisms in other cells both at the protein[89] and then at the epigenetic levels too.[95] 

Concluding remarks

Alzheimer’s and Parkinson’s diseases are two complex and very heterogeneous diseases with regards their underlying genetic aetiology, onset and pathology. The existence of rare fully penetrant mutations sufficient to cause each disease and that of common genetic polymorphisms conferring increased risk or modulating other aspects of the disease, have revealed many key molecular pathways and processes that are involved – to different extents – in the manifestation of both AD and PD. Even though, the quantitative contribution of each factor may not be clear, future approaches analyzing genetic variations within the context of molecular pathways, measurable biomarkers, epistatic and environmental interactions, genomic instability and mosaicism, may lead to a better characterization of the role that genetics play in the aetiology of PD and AD. However, the picture would be incomplete without integrating the findings from epigenetics. As summarized in Figure 4, it is probably the interplay between all these that ultimately determines the disease outcome, and evermore, the appreciation of the contribution of possibly multiple pathologic loops in AD and PD pathogenesis may inform future multiple target therapies. 

Figure 4. Interplay between genotype, epigenotype, environmental factors and pathology in complex diseases. Inherited or acquired, structural or sequence changes in a cell genotype can lead to altered gene regulation and protein expression. Similarly, gene regulation and protein expression can be further altered by global or specific epigenetic changes, which can be inherited, induced by early or late environmental factors and comorbidities or happen in a stochastic manner. Gene-gene interactions (epistasis) may play a role. All these deregulate several molecular pathways – possibly to different extends between different cells or individuals – and ultimately lead to the manifestation of pathological changes. Then these pathological changes can further alter the genotype (e.g. DND replication, failure of DNA repair, DNA breaks etc), further deregulate the cell epigenome and propagate the pathology to other cells by proteins with prion-like properties or even by inducing a cytotoxic environment (e.g. inflammation, oxidative stress). These pathological positive-feedback loops not only make it possible that a critical number of “seeding” cells with increased susceptibility can act as primary pathological foci and ultimately alter the susceptibility of neighboring cells but could also partially explain the histopathological variability observed, as different pathways may predominate in different cells or different individuals according to their prior risk factors. 

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