The SNCA gene encodes α-synuclein, a presynaptic protein of 140 amino acids that is involved in the compartmentalisation, storage, and recycling of neurotransmitters including dopamine. It also promotes membrane curvature, acts as a chaperone to the synaptic SNARE complex, and contributes to synaptic vesicle trafficking and dopamine release.33,34 The proteins potentially interacting with α-synuclein include chaperones/chaperonins, translocation factors, enzymes, mitochondrial-associated proteins, and proteins involved in secretion and degradation.35 It has been suggested that α-synuclein may modulate DNA repair.36 There is also evidence that it modulates intramitochondrial Ca2+ signalling, participates in mitochondrial fusion/fission, and is involved in electron transport chain complexes and axonal transport.37 Furthermore, its expression in immune cells and haematopoietic cells suggests a functional role in these processes.38

In its native state, α-synuclein occurs as a monomer, or as an α-helical homotetramer. The latter structure comprises 2 α-helices followed by an acidic C-terminal region, which is fundamental to interaction with other proteins: the first α-helix is positively charged and can bind to lipid membranes, whereas the second contains the non–amyloid-beta component, a hydrophobic region that enables the protein to form beta-sheets (Fig. 3A).33,35 The N-terminal acetylation or extension, comprising 10 amino acids, also results in tetramer formation, even without interaction with membrane phospholipids. The current paradigm suggests a dynamic equilibrium between these 2 conformational states.34

Fig. 3.

SNCA gene: molecular structure, genetic variants, and pathological forms of α-synuclein.

A) Amino acid sequence of SNCA; double helically folded tetrameric conformation of α-synuclein and the main PD-associated SNCA variants at the N-terminal domain. B) Different conformational states of α-synuclein and its aggregation in fibrils and Lewy bodies. Source: Fig. 3A taken from Post et al.76

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The accumulation in neurons of α-synuclein aggregates is believed to be a key process in PD pathogenesis. Patients present high levels of α-synuclein, with detergent-insoluble inclusions of the protein. The largest and most organised forms of these aggregates are incorporated in Lewy bodies, a pathological marker of the disease, which contain phosphorylated and ubiquitinated forms of α-synuclein (Fig. 3B).39 Accumulation mechanisms include defects in the proteasome degradation pathway, which may be reciprocally inhibited by the presence of oligomeric forms or fibrillary species of α-synuclein.40 The pathological role of α-synuclein in its different conformational states has been a subject of debate in recent decades. Some theories suggest that toxicity is mediated by excessive levels of abnormal α-synuclein (Fig. 4), or by loss of function of the protein in its native state.41

Fig. 4.

Pathways involved in the α-synuclein toxicity theory.

α-Synuclein toxicity has been linked to organelle dysfunction (yellow boxes), defects of inter-organelle contact (blue box), and dysfunction of organelle dynamics (orange box).

ER: endoplasmic reticulum.

Adapted from Wong and Krainc.77 (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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SNCA variants cause autosomal dominant parkinsonism with aggregation of α-synuclein, possibly due to accelerated fibrillation or oligomerisation, and progressive loss of nigrostriatal dopaminergic neurons.42SNCA A53T, described in 1997, was the first genetic variant associated with familial cases of PD,42 and is the most frequent point mutation, particularly in Italian and Greek families; it has also been reported in sporadic cases. Other point mutations include A30P (in German families), E46K (in Basque families), and more recently H50Q, G51D, and A53E.33 The different variants appear to be heterogeneous in terms of phenotype, pathological behaviour, and functional effects on α-synuclein (Table 3). Though rare, a growing number of cases of gene copy number variations (duplications and triplications) of SNCA have been reported.

SNCA-PD onset generally occurs in the fifth decade of life (<1% before 20 years of age and approximately 33% between 20 and 40 years and 66% after 40 years of age).43SNCA “burden” is correlated with age of onset, with a mean age of onset of 46.9 (10.5) years in patients with duplications and 34.5 (7.4) in those with triplications.44

According to data from literature reviews, over 70% of patients present rigidity and bradykinesia and 30%–80% present resting tremor43,45; the latter symptom is less frequent in patients with the SNCA A53T variant.46 Postural instability is observed in 89% of cases, and 83% present atypical signs (e.g., anterocollis/retrocollis, pyramidal signs, alien hand syndrome).43

Compared to idiopathic cases, SNCA-PD more frequently presents with dementia, hallucinations, and depression.45 Carriers of the A53T or E46K variants more frequently present dementia than carriers of the A30P variant, which is associated with milder phenotypes.34 56% of patients with multiplications report dementia in the first 5 years after onset of motor symptoms. Dementia onset is estimated to occur at 59 years and 42 years in carriers of duplications and triplications, respectively.44,47,48

Levodopa is usually effective,49 with up to 78% of patients responding well,43 although its effect may be short-lived. Among responders, 44% developed dyskinesia and/or motor fluctuations, and 24% presented dystonia.49

Psychotic symptoms were reported in 80%–95% of carriers of triplications and duplications, with heterogeneous rates reported in patients with point mutations (20%–76.2%).43,45,50

Depression is reported in approximately 22% of patients with SNCA-PD due to point mutations, 40%–56% of those with duplications, and 55%–100% of those with triplications.43,45

Autonomic signs are also frequent, occurring in 60% of patients with triplications, 40% with duplications, and 48%–56% of patients with the A53T variant.43,45 Some patients present severe orthostatic hypotension.46

Only weak evidence is currently available on other SNCA polymorphisms; a meta-analysis has associated some of these with increased risk of PD, including the rs2736990, rs356220, rs356165, rs181489, rs356219, rs11931074, and rs2737029 variants51; rs356219 is associated with a smaller effect on disease progression,52 whereas rs356195 may increase the risk of impulsive behaviour.53 In general, no association has been shown between the known SNCA polymorphisms and clinical heterogeneity of PD.

LRRK2 is a multi-domain protein belonging to the ROCO family. It includes domains regulating protein–protein interactions, such as the N-terminal armadillo repeat, ankyrin repeat, leucine-rich repeat, and the C-terminal WD40 domain. It also presents 2 enzymatic domains, the Ras of complex (ROC) GTPase domain and the serine/threonine kinase domain, separated by a C-terminal ROC domain. Familial mutations tend to affect catalytic domains.

Various functions have been attributed to LRRK2 due to its phosphorylation, via the kinase/GTPase domains, of over 20 substrates; these functions include cytoskeleton remodelling, protein expression, synaptic transmission, and membrane trafficking, among others.54

G2019S, the LRRK2 variant most frequently associated with familial PD, is associated with greater levels of kinase activity than in the wild-type protein. Other variants, such as R1441C/G/H and Y1699C, show increased binding to GTP, reduced GTP hydrolysis, and greater kinase activity. On the contrary, loss-of-function variants have not been found to increase the risk of PD.55

Cell and animal models have shown excess LRRK2 protein to be neurotoxic due to kinase-dependent mechanisms. Dysfunction of these pathways would facilitate the neurodegenerative process. In addition to the pathological detection of Lewy bodies in patients with LRRK2-PD, there is evidence that the protein is involved in pathogenesis through its molecular and functional relationship with α-synuclein.54 The identification of multiple Rab GTPases, G-proteins that regulate cellular vesicle trafficking, as physiological substrates of LRRK2 has given rise to an interesting hypothesis linking increased LRRK2 activity to cell-to-cell transmission of α-synuclein.54

Pathogenic variants of LRRK2 are risk factors for familial and sporadic (“idiopathic”) PD. LRRK2-PD is considered the most frequent form of monogenic autosomal dominant parkinsonism, presenting incomplete penetrance (age-dependent). Carriers of these variants account for 6%–40% of familial cases, depending on the ethnic group, and up to 2% of sporadic cases.54

A founder effect explains the accumulation of specific variants in certain populations, such as the G2019S variant in Ashkenazi Jew and Arab-Berber populations, with a south–north gradient in European countries; this is the most frequent variant worldwide. R1441G is the most frequent variant in the Basque Country, and displays a north–south gradient in Spain. Rarer pathogenic variants include Y1699C (reported in Germany, Denmark, Canada, and the United Kingdom), R1441C (Nebraska), I2020T (Japan), N1437H (Norway and Sweden), and R1441H.56 The G2385R variant has been identified as a risk factor in Japanese and Korean populations; in China, it is reported in 8%–11.7% of patients with PD and 0.5%–3.3% of the general population.57

The penetrance of G2019S is estimated at 25%–100% at 80 years of age,57 whereas the mean age of onset of LRRK2-PD is estimated at 57 years. Only 6% of patients present early onset.43

Generally, 88% of patients report tremor at some point during disease progression; similar figures are reported in carriers of the R1441G (76%) and G2019S variants (89%).43 Tremor is the initial symptom in 63% of patients with G2019S LRRK2-PD and 52% of idiopathic cases.58

In a cohort of patients of Ashkenazi Jewish descent with early-onset G2019S LRRK2-PD, a greater tendency to the postural instability/gait alteration phenotype was observed,59 with greater prevalence of falls compared to non-carriers.60

Dystonia, including “off” painful dystonia, is reported in 38%–42% of patients with LRRK2-PD, compared to approximately 25% of those with idiopathic PD.43,58

G2019S LRRK2-PD presents approximately 3 times greater prevalence of dystonia than idiopathic PD in the first 2 years, although, unlike in recessive parkinsonism, this rarely occurs before onset of dopaminergic treatment.

Atypical signs are rarely reported in LRRK2-PD (9%)43; as in idiopathic cases, 95% of patients respond well to levodopa,43,49 with 64% and 68% presenting dyskinesia and motor fluctuations, respectively.43 The latter symptom is more frequent in carriers of the R1441C/G/H variants than in those with other variants.43,61

Cognitive impairment and dementia appear to be less frequent in LRRK2-PD,47 only occurring in approximately 23% of patients,43,45 with dementia prevalence below the reported rate of 11%.48 Carriers of the G2019S variant present better attention, executive function, and language than non-carriers, after adjusting for phenotype.62

Psychotic symptoms are reported in 7%–32% of patients,43,45 whereas data on depression in G2019S carriers are controversial,63 with both higher and lower levels being reported than those seen in idiopathic PD.59,64,65

Patients with G2019S LRRK2-PD present higher rates of insomnia and lower rates of REM sleep behaviour disorder than in idiopathic cases.64 In a report of 18 cases of LRRK2-PD, 3 presented sleep attacks and 6 presented excessive daytime sleepiness.66

Autonomic signs are estimated to present in approximately 22.5% of patients with LRRK2-PD,45 with G2019S carriers presenting normal R-R interval variability67 and greater cardiac MIBG uptake; orthostatic hypotension is rarely reported.68

It has been suggested that patients with G2019S LRRK2-PD present greater risk of cancer than non-carriers, including skin cancer, leukaemia, breast cancer in women, and prostate cancer in men.69

VPS35 encodes vacuolar protein sorting ortholog 35 (VPS35), a subunit of the retromer complex, the main actor in the endosomal network (endoplasmic reticulum, Golgi apparatus, and endosomes); it is located in the early endosome and controls retrograde trafficking of cargo proteins from the early endosome to the trans-Golgi network or plasma membrane. The retromer complex also mediates vesicular transport from mitochondria to peroxisomes. This complex is the main centre that receives, dissociates, and sorts cargoes from different sources: (a) the plasma membrane (recycling of membrane receptors), (b) biosynthetic pathways (recovery of trafficking from the Golgi apparatus), and (c) the lysosomal pathway (direct trafficking to lysosomes). Generally, these activities control the homeostasis of transmembrane proteins at the plasma and endoplasmic levels, and regulate the abundance of receptors, signalling receptors, adhesion molecules, and hydrolase receptors.70

The retromer complex plays a role in neurodegenerative processes through its control of synaptic function and the trafficking and location of cargo proteins essential in neuronal homeostasis and in the balance between α-synuclein accumulation and clearance. VPS35 variants may cause PD through interference with α-synuclein degradation pathways.70

The prevalence of the D620N variant is estimated at approximately 1.3% in familial cases of PD and 0.3% in sporadic cases.71

VPS35-PD presents a mean age of onset of 50 (7.3) years,43,72 with early onset in only 7% of cases.43 Most patients respond well to levodopa. In a group of 8 responders, 4 reported dyskinesia, 5 presented motor fluctuations, and 2 displayed dystonia.43 Tremor is reported in 77%–98% of cases, and postural instability in 60%–67%, with no atypical signs.43,72

A review reported cognitive impairment in 44.5% of patients undergoing evaluation; however, after inclusion of patients for whom these data were missing, only 6% showed cognitive impairment.45 Psychotic symptoms appear to be less frequent (2/8 patients; 25%),43,45,63 whereas depression was reported in 10/15 patients (66.6%).45 Most of these patients present excessive daytime sleepiness,63 and a minority (4.5%) present autonomic signs.45