Page 123 - Read Online

SNCA (e.g. rs356165 and rs356219) with sporadic 0.5-5% in controls and confers at least two-fold risk for
PD, especially those from Southern Germany and the chance of PD. Given that this association appears
Asian. [44-47] Although molecular details are not clear, the robust across Asian populations, this risk allele is an
3’-variants have been shown to increase the expression underlying factor in a very large number of PD cases
of α-synuclein. [48] worldwide. More recently a second LRRK2 risk allele,
also identified within Asian PD populations has been
LRRK2 described. [64,65]
The discovery of mutations in the LRRK2 gene as
the cause of PD in the families linked to the PARK8 Microtubule associated protein tau
locus (12q12) was probably the most important The microtubule associated protein tau (MAPT) gene
step forward since the α-synuclein discovery. [49,50] encodes MAPT. Tau modulates the assembly, dynamic
LRRK2 is a very large gene that contains 51 exons, behavior, and spatial organization of microtubules, and
and over 30 sequence variants have been linked to is a major protein component of neurofibrillary tangles,
autosomal-dominant Parkinsonism. However, only a hallmark lesion of Alzheimer’s disease (AD). Mutations
five (R1441C, R1441G, Y1699C, G2019S, and I2020T) in the MAPT gene were identified to cause autosomal
have been shown or be clearly pathogenic, and two dominant frontotemporal dementia with parkinsonism
[66]
substitutions (G2385R, R1628P) have been associated linked to chromosome 17. In addition to rare causal
with an increased risk for sporadic PD. mutations, common variability in MAPT has been
linked to disease such as progressive supranuclear palsy,
The most common LRRK2 mutation is Gly2019Ser. AD and PD. The most frequently reported variation is
It is detected in about 5% of familial and 1-2% caused by a common genomic inversion within a large
of sporadic European PD patients [51,52] and up to block (approximately 1.6 Mb in length) containing the
30% of patients with PD from North African and MAPT locus that shows reduced recombination and
10-40% of Middle Eastern populations. [53-56] One high levels of linkage disequilibrium. This phenomenon
intriguing feature of this mutation is its association results in two common Caucasian haplotype groups
with both familial and sporadic PD. However, across this locus, often termed H1 and H2. Association
the penetrance of this mutation is relatively low. between MAPT H1 and risk for PD has been tested by many
By analyzing the pooled data of 24 populations groups, [67,68] and the results in general show a consistent
worldwide (including 19,376 unrelated patients with association with the disease. Moreover, patients carrying
PD), the International LRRK2 Consortium reported the H1 allele present in their fifth decade either with
the risk of PD for a person who inherits the LRRK2 behavioral/cognitive changes or with rapidly progressive
G2019S mutation was 28% at age 59 years, 51% and poorly levodopa-responsive parkinsonism. A recent
at 69 years and 74% at 79 years. Although motor follow-up study demonstrated that 17% of incident
and nonmotor symptoms of LRRK2-associated PD PD patients developed dementia over 5 years, and the
were more benign than those of idiopathic PD, the MAPT H1/H1 genotype was an independent predictor
core features (asymmetrical, tremor predominant of dementia risk (odds ratio = 12.1). [69] The results
parkinsonism with bradykinesia and rigidity that also suggested that Lewy body deposition in posterior
responded to dopamine) of the patients with LRRK2 cortical areas, which is influenced by MAPT genotype
G2019S-associated PD are indistinguishable from and the aging process are associated with subsequent
patients with idiopathic PD, again implying a critical global cognitive decline and dementia. However, the H1
contribution of LRRK2 to the PD pathogenesis. [57] haplotype may not be a universal risk allele because the
H2 haplotype is almost exclusively Caucasian in origin,
Although the G2019S is prevalent in PD patients and its prevalence in other populations is essentially
in the above-mentioned populations, it does not zero. [70]
occur at appreciable frequency in control cohorts
from these populations and is strikingly rare in In addition to the H1 haplotype, a subhaplotype
Chinese [58,59] and South African. [60] Therefore, it is within the H1 clade composed of two “H1-SNPs”
more a population-specific mutation than a popular (rs242562 and rs2435207) spanning MAPT exons
susceptibility variant. In contrast, two variants reported 1-4 was also significantly overrepresented in cases
from Asian populations appear to be true risk variants versus control subjects. [71,72] However, except for in
for PD. The first G2385R was initially described in a one Greek and one Nowegian study, the association of
Taiwanese family. [61] Assessment of this variant in large H1-subhaplotype with PD was not well replicated in
Asian populations showed association with risk for other Caucasian studies, and Taiwan Chinese, [68,73,74]
disease in Taiwanese, Japanese, Hong Kong Chinese and it has not been tested whether this subhaplotype is
and mainland Chinese populations. [61-63] In general this associated with PD in populations that possess merely
variant is present in about 10% of PD populations and the H1 clade.

Neuroimmunol Neuroinflammation | Volume 1 | Issue 3 | December 2014 117