Fig. 1.1
Schematic representation of defined loci and genes for PD, including Mendelian genes and loci identified by association studies. The loci, gene symbols, and chromosomal position are indicated. EO-PD early-onset Parkinson’s disease, GWAS genome-wide association studies
This review focuses on the genes which have been conclusively associated with Mendelian forms of the disease, highlighting the most recent advances in this field of research.
Autosomal Dominant Forms of Mendelian PD
The two autosomal dominant genes, SNCA and LRRK2, which confer a gain of function that is neurotoxic for dopaminergic neurons, are now known to be of major importance in the pathogenesis of both familial and sporadic PD. VPS35 and EIF4G1 were identified only recently, and the role they play remains unknown. Other disease-causing genes, such as repeat expansions in ataxin-2 (ATXN2) and ataxin-3 (ATXN3), which cause spinocerebellar ataxias; guanosine triphosphate cyclohydrolase 1 (GCH1), which causes dopa-responsive dystonia; hexanucleotide expansions in C9orf72, which cause frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS); and heterozygous mutations in the β-glucocerebrosidase (GBA) gene, which are responsible for a recessive disorder, Gaucher’s disease, have been associated with typical parkinsonism.
LRRK2
Mutations in LRRK2 are the most common cause of dominantly inherited PD and explain up to ~10 % of all familial forms of the disease with clearly dominant inheritance [1, 2]. The LRRK2 gene, which spans a genomic region of 144 kb containing 51 exons, encodes a large 2,527-amino-acid protein with two enzymatic domains (GTPase and kinase) and multiple protein-protein interaction domains [3]. About 80 different LRRK2 variants have been reported worldwide. Only 7 of these LRRK2 mutations (N1437H, R1441G/C/H, Y1699C, G2019S, and I2020T), which appear to be clustered in functionally important regions that are highly conserved through evolution, have been proven to be pathogenic on the basis of co-segregation with the disease and their absence or rarity in specific control populations [4]. Some of them are strikingly population specific. The most common G2019S mutation in the kinase domain of the protein is particularly enriched in Arab patients from North Africa (30–40 %) [5] and in Ashkenazi Jewish PD patients (10–30 %) [6] and probably arose from a common ancestor in the Middle East [7]. The R1441G substitution in the ROC GTPase domain appears to be geographically restricted to Northern Spain, particularly the Basque population, in which it is responsible for ~20 % of familial PD [1, 8, 9]; however, the same mutation was recently reported on a different haplotype in a Japanese family [10]. I2020T was originally identified in a Japanese kindred [11]. The most recently identified mutation, N1437H, was originally described in two Norwegian families [12] and a Swedish PD patient [13]. Common polymorphisms in LRRK2, such as G2385R, R1628P [14], and, more recently, A419V [4], may be strong risk factors for sporadic PD in Asian populations. In contrast, the LRRK2 M1646T mutation seems to be a common polymorphism that is specifically associated with PD in Caucasian populations [4]. In both Asian and Caucasian populations, genome-wide association studies (GWAS) identified risk factors in the 5′ region of the LRRK2 gene in sporadic PD [15, 16].
Penetrance of the most common G2019S mutation, which is incomplete and age-dependent, ranges from ~25 to 70 % at age 80 years [17–19], explaining the frequency of its occurrence in sporadic PD patients [20], in families with apparently autosomal recessive inheritance [21], and in healthy mutation carriers over 80 years of age [22]. Homozygous G2019S mutation carriers were also identified among healthy elderly subjects [23].
The clinical features of patients with the G2019S mutation are surprisingly uniform and resemble those of patients with typical late-onset PD. The mean age at onset is close to 60 years, with unilateral tremor as the initial sign of disease, a good response to treatment, and slow progression [17]. Atypical features, such as amyotrophy, dystonia, supranuclear gaze palsy, primary progressive aphasia, or corticobasal syndrome, have also been reported [24–26]. Some homozygous mutation carriers, mostly among North African Arabs, are clinically similar to those with heterozygous mutations [23, 27], indicating an absence of gene dosage. In contrast to the clinical homogeneity of patients with LRRK2 mutations, the associated pathology is remarkably variable, even within a given family. Most patients with the G2019S mutation have neuronal loss in the substantia nigra and α-synuclein-positive Lewy bodies as in typical PD; in some cases, nigral degeneration without Lewy bodies, diffuse Lewy body disease, and tau pathology have been observed [25, 28–31].
LRRK2 is a ubiquitous protein of unknown function. Many studies have focused on its GTPase and kinase activities and have shown that mutations in the kinase domain (G2019S, I2020T) increase kinase activity, whereas those in the ROC GTPase domain decrease GTPase activity [32]. Because of the increase in kinase activity associated with LRRK2 mutations, LRRK2 kinase inhibitors have been developed as a potential treatment for PD [33]. LRRK2 plays a role in multiple cell functions, including intracellular trafficking, cytoskeletal dynamics, mitochondrial function, autophagy regulation, and, recently, a cellular pathway related to the immune system and regulation of neuroinflammation [34].
α-synuclein
SNCA mutations are the second most common cause of dominantly inherited PD; genomic duplications have been detected in ~1–2 % of the PD families with autosomal dominant inheritance [35, 36]. Other SNCA mutations are extremely rare and include whole-locus triplications [37] and point mutations; A53T was identified in a few families of Greek ancestry and also in families and apparently sporadic cases of European and Asian origin [38–43]. A30P and E46K were each identified in a single family of German and Spanish origin, respectively [44, 45]. Very recently, five new rare missense variants (A18T, A29S, H50Q, G51D, and A53E) were identified in PD patients. H50Q was found in one isolated case of English origin who had pathologically confirmed PD [46] and one Canadian case of English/Welsh origin who had a family history of parkinsonism and dementia [47]; the mutation arose from a common ancestor. G51D cosegregated with the disease in two independent families of French and English origin [48, 49] and in an isolated case of Japanese origin with family history of parkinsonism and dementia [50]. A53E was found in a Finnish family associated with atypical multiple system atrophy and PD [51]. A18T and A29S were detected in single patients of Polish origin presenting with a typical late-onset sporadic PD phenotype, but their pathogenicity has not been proven [52].
Postmortem examination of brains from patients with SNCA mutations revealed consistent neuronal loss and an abundance of α-synuclein-positive Lewy bodies and neurites in the substantia nigra and locus ceruleus, but limbic and glial abnormalities are also observed; pathologies associated with both PD and multiple system atrophy (MSA) may overlap [48, 49, 51, 53]. In contrast, the associated clinical spectrum is broad, ranging from typical late-onset PD, generally observed in patients with genomic duplications as well as those with H50Q mutations, to atypical PD, characterized by more severe features, including an earlier age at onset (<40 years), myoclonus, more rapid progression, and a high prevalence of dementia and autonomic dysfunction, observed in patients with rare genomic triplications and A53T/E, E46K, or G51D missense mutations. In view of the overlapping clinical features, it has been proposed that PD, parkinsonism with dementia, dementia with Lewy bodies, and MSA are causally related and are collectively referred to as “synucleinopathy” disorders.
Common variants in SNCA that may influence the expression of the disease [54, 55] have been found to be the most consistent and robust risk factors in large, population-based, multiethnic sporadic PD in all GWAS conducted so far, as well as in subsequent meta-analyses [56–60].
α-Synuclein is a 140-residue natively unfolded protein that is abundantly expressed in presynaptic nerve terminals [61]. It consists of three domains: an amino-terminal lipid-binding α-helix characterized by seven imperfect repeats (KTKEGV), a non-amyloidogenic core (NAC) domain, and an unstructured carboxy-terminus. Interestingly, most of SNCA mutations are clustered in the amphipathic alpha helical domain, suggesting a mutational hotspot. Although its physiological function is not fully known, it appears to be particularly prone to rapid conformational changes and has been implicated in the regulation of synaptic transmission and dopamine biosynthesis. The aggregation dynamics of mutant SNCA has been reported to be faster or slower than wild-type SNCA, suggesting that the process of aggregation is related to SNCA-induced neurotoxicity [62].
Recently Identified Genes Causing Autosomal Dominant PD
Recently, three new genes were reported to cause autosomal dominant PD. VPS35 was the first PD-causing gene identified by exome sequencing. The same D620N mutation was originally reported, by two independent groups, to segregate in two large kindreds of Swiss and Austrian origin, respectively [63, 64]. Subsequent studies in multiple ethnic groups, including a large multicenter study [65, 66], indicated that the VPS35 D620N mutation rarely causes autosomal dominant PD; the frequency ranges from 0.1 to 1 %, with an overall frequency lower than 0.1 % (24/22,612). It was absent from >16,000 healthy controls [67]. Like LRRK2 mutations, the VPS35 D620N mutation was found in rare sporadic cases [68] and unaffected individuals over 80 years of age [63], indicating reduced penetrance. Haplotype analyses suggest that this mutation arose independently by recurrent mutational events [63]. Mutational screening of the entire coding regions has not revealed any other variants with unequivocal pathogenicity [64, 66, 69]. Patients with VPS35 mutations have typical levodopa-responsive PD but with a slightly earlier age at onset (on the average in the fifth decade of life) [67]. The VPS35 gene encodes a subunit of the retromer complex involved in endosomal-lysosomal trafficking and recycling of synaptic vesicles and proteins. Mutations in VPS35 may result in impaired cargo recognition and binding and thus defective receptor recycling.
Exome sequencing was recently used to identify a new N855S mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13); it segregated with the disease in a multi-generation Mennonite family of 118 family members in which 13 affected individuals were sampled [70]. This mutation was subsequently found in two small families and two isolated cases with a common ancestral haplotype but was not identified in >2,600 controls. The phenotype was consistent with a late-onset asymmetric PD, although rare cases had dementia and neuropathology consistent with brainstem or transitional Lewy body disease. However, due to incomplete penetrance and the presence of phenocopies in the large family and the lack of further studies on DNAJC13 mutations, proof that DNAJC13 causes PD is still lacking. DNAJC13 plays a role in endosomal trafficking by regulating the dynamics of clathrin coats on early endosomes. Preliminary functional analyses showed that the DNAJC13 N855S mutation confers a toxic gain of function that impairs endosomal transport.
A traditional linkage study in a large French family in which an R1502H mutation in EIF4G1 segregated with the disease identified eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) to be another new cause of dominantly inherited PD [71]. The same R1502H mutation and another missense variation, A502V, were found in a few small families of European and North African descent with mutation frequencies of 0.2 and 0.02 %, respectively, as were additional single variants, G686C, S1164R, and R1197W. However, most subsequent studies failed to replicate these findings, and some found the two most common EIF4G1 mutations in healthy controls [72, 73]. The associated phenotype was late-onset PD with a good response to levodopa and neuropathology consistent with brainstem Lewy body disease [71]. The encoded protein, EIF4G1, is a central component of the eIF4F complex that regulates mRNA translation and might be involved in the stress response. Functional analyses demonstrated that the two most frequent EIF4G1 variants, R1502H and A502V, impair formation of the multi-subunit complex, compatible with a dominant-negative mechanism of action [71].
SCA/Ataxins, GBA, GCH1, c9orf72: Risk Factors or Dominant Causal Genes?
Trinucleotide expansions in SCAs/ataxins cause autosomal dominant spinocerebellar ataxias with a broad phenotype that often includes parkinsonism; however, the parkinsonism may also be pure, particularly in SCA2 or SCA3 carriers. The frequency of SCA2 mutations in familial parkinsonism ranges from 1.5 to ~10 %, and seems to be particularly high in patients of Asian origin [74–77]. In these patients, parkinsonism may range from typical levodopa-responsive PD to Parkinson-plus phenotypes. The configuration of the SCA2 repeat expansion has recently been shown to play an important role in phenotypic variability. Whereas uninterrupted CAG repeat expansions are associated with ataxia, shorter expansions interrupted by CAA triplets are associated with parkinsonism [75, 78]. More rarely, repeat expansions in SCA3 have also been associated with a phenotype resembling pure parkinsonism without prominent ataxia [79].
Candidate gene association studies identified heterozygous mutations in GBA as solid risk factors for PD although, in the homozygous or compound heterozygous state, the same gene causes Gaucher’s disease (GD), a recessive lysosomal storage disorder. Historically, the occurrence of parkinsonism and Lewy body pathology in patients with GD and their relatives and the identification of GBA mutations in patients with PD indicated that there was a link between GD and PD [80]. GBA mutations cause an ethnic group-dependent increase in the risk of developing PD, accounting for ~7 % of Caucasian PD patients and up to 8 % in patients with family history of PD [81]; they are found in only ~1 % of control subjects. The frequency is much higher in Ashkenazi Jews, reaching ~20 % in PD patients versus 4 % in controls [82]. The clinical phenotype resembles that of typical late-onset PD with widespread and abundant α-synuclein pathology and prominent diffuse neocortical Lewy body pathology [83]. However, the greater the family history of PD, the earlier the disease begins and the more severe the non-motor symptoms, including more marked and rapid cognitive impairment [81, 82, 84] and a relatively high penetrance of PD among GBA mutation carriers [85]; this suggest that GBA could be a dominant causal gene with reduced penetrance rather than a risk factor. The mechanisms by which GBA mutations exert their pathogenic effects or act as risk factors for PD are not yet understood. Effects on lysosome function, ceramide metabolism, the ubiquitin-proteasome system, or lipid metabolism have been postulated in relation with α-synuclein clearance [86].
Mutations in the candidate gene, guanosine triphosphate cyclohydrolase 1 (GCH1), are the most common cause of levodopa-responsive dystonia (DYT5) [87], a rare movement disorder starting in childhood with sustained response to small doses of levodopa, but also cause adult-onset parkinsonism in the absence of dystonia [88]. A recent multicenter study identified rare GCH1 variants as risk factors for PD (odds ratio (OR) 7.5, confidence intervals (CIs) 2.4–25.3) [89].
Parkinsonism has been described in some individuals with hexanucleotide repeat expansions in C9orf72 that are now recognized as the most frequent cause of frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS) [90, 91]. Parkinsonism related to this mutation may present as typical idiopathic PD without any signs of dementia [92].
Autosomal Recessive Forms of Mendelian PD
One of the most important findings of these last years was the relatively high proportion of patients with early-onset parkinsonism caused by recessively inherited mutations in numerous genes: parkin/PARK2, PINK1/PARK6, and DJ–1/PARK7. More recessive genes were recently identified in a few patients with early-onset atypical parkinsonism: ATP13A2/PARK9, PLA2G6/PARK14, FBXO7/PARK15, DNAJC6, and SYNJ1/PARK20.
Parkin
Homozygous exon deletions in the parkin gene at the PARK2 locus were first described, in 1998, in consanguineous Japanese families with a syndrome previously known as autosomal recessive juvenile parkinsonism, which is characterized by young onset (<20 years) in most cases, a good response to levodopa, and the frequent occurrence of levodopa-induced dyskinesias [93]. Subsequent screening of this large gene, which spans 1.3 Mb of genomic DNA, for both point mutations and exonic rearrangements showed that homozygous and compound heterozygous mutations in the parkin gene are the most common cause of early-onset PD (<45 years) in populations of all ethnic origins; it accounts for ~50 % of recessive familial forms with onset before age 25 years and ~15 % of isolated cases in European populations. Interestingly, the frequency of parkin mutations decreases as the age at onset increases; parkin mutations are therefore uncommon in patients with late-onset PD. More than 100 different mutations have been identified throughout the gene; they comprise large deletions or duplications and triplications of one or more exons in more than 50 % of the reported cases, but small deletions/insertions, nonsense, and missense mutations are also found. In addition, heterozygous parkin mutations have been reported in sporadic, late-onset PD and may constitute genetic risk factors.
Clinically, PD patients with parkin mutations have classical PD but, compared to patients without parkin mutations, earlier and more symmetrical onset, usually with dystonia, hyperreflexia, slower disease progression, sleep benefit, and a better response to low doses of levodopa, complicated by early motor fluctuations, the development of dyskinesias, and, in rare cases, atypical features, such as psychiatric manifestations [94]. In contrast to patients with typical forms of PD, PD patients with parkin mutations have a severe loss of dopaminergic neurons in the substantia nigra and locus ceruleus and gliosis but, in general, no Lewy bodies. Thus, nigral cell loss in PD patients with parkin mutations appears to be caused by a loss of function of the protein. The parkin gene encodes a cytosolic 465-amino-acid protein containing an ubiquitin-like (UBL) N-terminal domain, followed by three RING (really interesting new gene) finger motifs separated by an IBR (In-Between-Ring) domain in the C terminus. Parkin is an E3 ubiquitin ligase responsible for the transfer of activated ubiquitin molecules to a protein substrate [95], a signal for proteosomal degradation of the protein. Mutations in parkin were reported to impair the E3 ubiquitin ligase activity of Parkin, resulting in insufficient protein clearance and the subsequent formation of protein aggregates [95].
PTEN-Induced Kinase 1 (PINK1)
PINK1 was first mapped at the PARK6 locus, in 2004, in three consanguineous families with autosomal recessive early-onset PD [96]. Following these findings, more than 50 homozygous and compound heterozygous mutations have been found in the PINK1 gene, ranging from frameshift, truncating, and splice site point mutations to deletion of the entire PINK1 gene. PINK1 is, therefore, the second most frequent known cause of autosomal recessive early-onset parkinsonism after parkin (1–8 % mutation frequency). PINK1 mutations are also a rare cause of sporadic early-onset PD [97].
The clinical phenotype of PINK1-related disease appears broadly similar to that of parkin-related disease but usually with a later age at onset; there may also be a higher prevalence of psychiatric disturbances [98]. The neuropathological manifestations in a single patient with compound heterozygous mutations in PINK1 resemble Lewy body and Lewy neurite pathology [99]. The PINK1 gene encodes a 581-amino-acid protein, containing a 34-amino-acid mitochondrial targeting motif and a highly conserved protein kinase domain that has homologies with the calcium/calmodulin family of serine/threonine kinases [96]. Most of the described mutations lie near or within the functional serine/threonine kinase domain of PINK1. These mutations reduce or impair kinase activity, accelerate degradation, or induce misfolding of the protein.
DJ-1
The third locus for autosomal recessive early-onset parkinsonism, PARK7, was mapped in a Dutch family [100]; the PD-causing gene was identified, in 2003, as the oncogene DJ-1. A DJ–1 missense mutation (L166P) and large exonic deletions were first identified in two European families with early-onset PD [101]. A number of other pathogenic mutations causing familial PD were later identified but are responsible for the disease in less than 1 % of early-onset PD patients. Clinically, onset of PD in patients with DJ–1 mutations occurs in the third decade, with asymmetric symptoms, slow disease progression, and a sustained response to levodopa treatment. No neuropathological studies of DJ–1 patients have as yet been reported. The DJ–1 gene encodes a highly conserved 189-amino-acid protein of the ThiJ/Pfp1 family of molecular chaperones that are induced during oxidative stress.
Other Forms of Early-Onset Recessively Inherited Atypical Parkinsonism
Mutations in the neuronal lysosomal P-type ATPase (ATP13A2) in the PARK9 locus, calcium-independent phospholipase A2, group VI (PLA2G6) in PARK14, and F-box only protein 7 (FBXO7) in PARK15 cause recessively inherited forms of atypical parkinsonism characterized by juvenile to early-onset, poor response to levodopa and variable combinations of additional clinical signs: dystonia, cognitive impairment, neurobehavioural abnormalities, pyramidal disturbances, ophthalmoparesis, and autonomic dysfunction. Of note, mutations in ATP13A2 are associated with Kufor-Rakeb syndrome (KRS), a form of recessively inherited, juvenile, multisystemic parkinsonism, characterized by rapid disease progression, pyramidal signs, dementia, and supranuclear gaze palsy [102]. Recessive mutations in PLA2G6 are also associated with other childhood or young adult-onset syndromes, including infantile neuroaxonal dystrophy (INAD) [103], idiopathic neurodegeneration with brain iron accumulation (NBIA) [104], and adult-onset parkinsonism with dystonia and pyramidal involvement [105]. Mutations in FBXO7 cause a complex combination of pyramidal and extrapyramidal syndromes, predominantly characterized by childhood-onset dystonia [106]. The ATP13A2 gene encodes a large transmembrane protein with putative ATPase activity located in lysosomes, further linking abnormal function of these organelles to neurodegeneration. PLA2G6 encoding a group VI calcium-independent A2 phospholipase, which catalyzes fatty acid release from phospholipids, may be implicated in inflammatory responses and apoptosis [107]. The FBXO7 gene encodes a member of the F-box family of proteins, which play a role in the ubiquitin-proteasome protein degradation pathway. Very recently, recessive mutations in DNAJC6 and SYNJ1 were shown, by homozygosity mapping and exome sequencing, then subsequent replication in other studies, to cause autosomal recessive juvenile parkinsonism in rare families [108–112]. DNAJC6 encodes auxilin, a clathrin-associated protein and SYNJ1 encodes synaptojanin 1, both of which may be implicated in the recycling of synaptic vesicles.
Conclusion
The discovery of mutations [38] and, later, gene multiplications in SWCA [37], which cause dominant forms of PD, triggered 15 years of gene discoveries and new efforts to model parkinsonian neurodegeneration. Although, Mendelian forms of PD account for only a small proportion of PD cases, it is now clear that the genetic component of PD plays a much more important role in the pathogenesis of PD than previously thought. Notably, studies of PD-linked genes in some heritable forms of PD have brought to light several molecular abnormalities in the substantia nigra that are associated with neuronal death: protein aggregation, defects in the ubiquitin-proteasome pathway, impaired defenses against oxidative stress, abnormal protein phosphorylation, mitochondrial and lysosomal dysfunction, apoptosis, and now defective post-endocytic recycling of synaptic vesicles, thus improving our understanding of the more common sporadic form of the disease. An illustration is offered by LRRK2 and SNCA that contain both rare, highly penetrant variants and common, weakly penetrant variants, suggesting that Mendelian forms of PD might also explain common non-Mendelian forms of PD, and vice versa.
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