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practice, with emphasis on large-scale and multiethnic SNCA in these patients, the cause of PD appears to be
evidences, as listed in Table 1. the mere increase in α-synuclein levels. In support of
this dosage effect, PD patients from families with two
GENETIC VARIATIONS WITH WELL‑EVIDENCED extra copies of SNCA have a more severe phenotype
ASSOCIATIONS WITH PARKINSON’S DISEASE than PD patients with only one extra copy, [25,27,31] and
SNCA mRNA levels in the brain from sporadic patients
SNCA are increased. [32-35]
Genetic variability within the SNCA gene encoding
α-synuclein is arguably the most reliable association The pathogenicity of multiple SNCA gene copies and
of a common genetic risk factor with PD identified to the apparent dosage effect of α-synuclein levels in
date. Although mutations in this gene account for < 1% both sporadic and familial PD highlight the clinical
of PD in the general population, abnormal aggregation significance of the regulation of SNCA gene expression,
of the SNCA-encoding protein, α-synuclein, the which can take place at both transcriptional and
principal component of Lewy bodies, is present in all posttranscriptional levels. Transcription of genes is
patients with idiopathic PD. [16] In addition, association mainly regulated by the promoter sequence. The first
studies have repeatedly suggested the link of the SNCA promoter variant reported in association with PD
variations to both familial and sporadic PD. Further, was the mixed dinucleotide repeat sequence (REP1),
several most recently completed GWAS consistently which resides approximately 10 kb 5′ to the translation
showed strong linkage of the SNCA locus to PD across start site of SNCA. Despite some negative results of
Western and Oriental populations. [12-15] association, the majority of individual studies [36-39] and
a meta-analysis of data [40] from 18 sites across multiple
Although three missense mutations in SNCA were ethnic populations have confirmed an association
reported in families with PD inheritance [18-20] and between risk for PD and the longer REP allele. In addition,
thought to increase the aggregation of SNCA protein, variants other than REP1 in the promoter region, such
point mutations have not been identified in sporadic as SNPs flanking the core promoter at the -770 and -116
PD, [21,22] and no several nonsynonymous (SNPs) positions, rs2583988, rs2619364, and rs2619363, were
have been found in the coding region, suggesting also reported to increase the susceptibility to PD in
that disease-related amino acid changes in SNCA are European population. [41] Posttranscriptional regulation
unlikely in sporadic PD. [23] In contrast, multiplication, of gene expression can be mediated by several elements,
in particular triplication, of SNCA was revealed in many of which are located in the 3’-untranslated
both familial [24-29] and sporadic PD cases. [30] Due to region of mRNAs. [42,43] A series of studies reported
the absence of point mutations in any of the copies of an association of polymorphisms at the 3’-end of

Table 1: Genes and loci related to Parkinson’s disease
Locus Gene Chromosome Inheritance Type of parkinsonism Mutation/varaint Association with PD
type
PARK1/PARK4 SNCA 4q21 AD LOPD/EOPD, dementia Multiplication, point Convinced
PARK2 Parkin 6q25‑27 AR EOPD Re‑arrangement, point Re‑arrangement: convinced;
point: unconvinced
PARK3 Unknown 2p13 AD LOPD Point Unconvinced
PARK5 UCHL1 4p14 AD LOPD Deletion, point Unconvinced
PARK6 PINK1 1p36 AR EOPD Deletion, point Unconvinced
PARK7 DJ‑1 1p36 AR EOPD Deletion, point Unconvinced
PARK8 LRRK2 12q12 AD LOPD Point Convinced
PARK9 ATP13A2 1p36 AR EOPD, Kufor‑Rakeb Point Unconvinced
syndrome
PARK10 Unknown 1p32 Unknown LOPD Point Unconvinced
PARK11 GIGYF2 2q37 AD LOPD Point Unconvinced
PARK12 Unknown xq21‑25 X‑linked LOPD Point Unconvinced
PARK13 HTRA2 2p12 AD LOPD Point Unconvinced
PARK14 PLA2G6 22q13 AR EOPD, Point Unconvinced
dystonia‑parkinsonism
PARK15 FOXB7 22q12‑13 AR EOPD, pallido‑ Point Unconvinced
pyramidal syndrome
PARK16 Unknown 1q32 Risk LOPD Point Unconvinced
PARK17 VPS35 16q11 Risk LOPD Point Unconvinced
PARK18 EIF4G1 3q27 Risk LOPD Point Unconvinced
‑ GBA 1q21 Risk LOPD Point Convinced
‑ BST1 4p15 Risk LOPD Point Unconvinced
‑ MAPT 17q21 Risk LOPD Haplotype Convinced
‑ ATXN2 12q12 Risk LOPD Trinucleotide expansion Unconvinced
‑ ATXN3 14q32 Risk LOPD Trinucleotide expansion Unconvinced
AD: autosomal dominant; AR: autosomal recessive; EOPD: early‑onset Parkinson’s disease; LOPD: late‑onset Parkinson’s disease; PD: Parkinson’s disease

116 Neuroimmunol Neuroinflammation | Volume 1 | Issue 3 | December 2014