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Advanced Neurology Alpha-synuclein, depression and neurodegeneration

2. Materials and methods Table 1. Functional polymorphisms of the alpha‑synuclein
gene SNCA analyzed in the current study and their
2.1. Materials significance
The Global Burden of Disease Study, which began in the year Polymorphism Functional significance Data
1990 and was most recently updated in 2019, represents a availability
systematic attempt to estimate the prevalence, burden, and rs356220 (C/T) Known to be associated with an 18 countries
outcome associated with diseases and their risk factors at a increased risk of Parkinson’s disease in
global level . Data on the estimated prevalence of depressive both European and Asian populations
[50]
[67]
disorders (major depressive disorder [MDD] and dysthymia), and more severe cognitive decline in
PD, and AlzD and related dementias were retrieved for the Parkinson’s disease [68]
years 1990 and 2019 through database queries from the rs2736990 (T/C) Known to be associated with 32 countries
Global Health Data Exchange, which provides access to the an increased risk of Parkinson’s
entire data set of the Global Burden of Disease Study . MDD, disease, especially in East Asian
[51]
populations , and altered levels of
[69]
which is characterized by distinct episodes of depression with specific SNCA transcripts [68]
total or partial inter-episode recovery, has been consistently rs3775439 (G/A) The minor allele (A) is known to be 32 countries
associated with both PD and AlzD [32-34] . Since older research associated with an increased risk of
has suggested that dysthymia may be associated with PD , it Parkinson’s disease in the elderly
[52]
[70]
was also included in the analyses. and may interact with other genes
to influence the risk of developing
Several polymorphisms of SNCA gene have been Parkinson’s disease [71]
associated with the risk or symptomatology of PD [53,54] .
Although the association between this gene and AlzD has Among the environmental risk factors linked to both PD
not been subjected to a comparable level of study, there is and AlzD, air pollution and pesticide exposure have shown
both direct and indirect evidence that variants in SNCA to be the most consistently replicated associations [67-69] .
are correlated with the risk of AlzD and its underlying Environmental air pollution, particularly exposure to
pathophysiology [55-58] . Recent research has suggested particulate matter with a diameter of ≤2.5 microns (PM2.5),
that SNCA may also be a candidate gene for major has been associated with significantly increased risk for
depression . In light of these findings, the relationship both PD and AlzD in studies across 26 countries and
[59]
[70]
between selected functional polymorphisms of the SNCA increased rates of depression . Cumulative exposure to
[71]
gene and the prevalence of major depression, PD, and pesticides is associated with an approximately 50% relative
AlzD was examined at a population level. risk increase for both PD and AlzD ; there is also evidence
[72]
[73]
For the purpose of this analysis, data on allele of a link between pesticide exposure and depression .
frequencies for these polymorphisms were obtained from Genetic factors may partially mediate the association
[74]
the Allele Frequency Database, a public-domain repository between pesticide exposure and PD . Therefore, the
that contains data on over 660,000 genetic polymorphisms effect of these two environmental factors on the possible
in 762 distinct populations [60,61] . Although this database associations between depression, PD, and AlzD was also
contains data on several polymorphisms of SNCA, most examined in the current study through epidemiological
of them are of unknown functional significance. Only and population genetic analyses. Information on the
polymorphisms that fulfilled the following criteria were PM2.5 levels of each of the 193 countries and regions
[75]
selected for analysis: under the WHO’s Global Health Observatory and data
on the levels of pesticide exposure, measured in terms of
(i) Evidence of an association of the specific average pesticide application (in kilograms) per unit of
polymorphism with either the disorders being studied cropland (in hectares), were obtained from the Food and
or with their clinical manifestations based on human Agriculture Organization’s FAOSTAT database .
[76]
genetic studies;
(ii) Availability of data for diverse populations across 15 2.2. Methods
or more countries. The identification of a positive correlation between the
On the basis of these criteria, the following functional prevalence of distinct disorders across populations is
single-nucleotide polymorphisms (SNPs) of SNCA suggestive, but not confirmatory, of a significant association
were selected for analysis: rs356220, rs2736990, and between them. Such an association may also arise by
rs3775439. Details of the functional significance of these chance or may be related to confounding factors . Similar
[77]
polymorphisms and the availability of allele frequency data concerns arise when attempting to correlate putative
for each of them are shown in Table 1 [62-66] . risk factors, either genetic or environmental, with the

Volume 2 Issue 1 (2023) 3 https://doi.org/10.36922/an.326