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Advanced Neurology Alpha-synuclein, depression and neurodegeneration

Table 8. General linear model analyses of changes in Parkinson’s disease and Alzheimer’s disease over the period 1990 – 2019
Variable Time (1990 – 2019) MDD Dysthymia Depression rs356220 rs2736990 rs3775439
Parkinson’s disease, change over time 197.78 a 10.05 a 47.30 a 21.28 a 3.89 3.69 0.66
Alzheimer’s disease, change over time 147.24 a 13.02 a 30.98 a 22.48 a 1.21 2.47 0.68
MDD: Major depressive disorder. All test statistics were given as repeated measures analysis of variance (RMANOVA) or repeated measures analysis of
covariance (RMANCOVA) test statistic (F). Significant at P<0.05
a
in patients with AlzD . Although no studies linking these disorders. A large-scale analysis of genome-wide
[12]
dysthymia to the levels of α-synuclein or SNCA gene have association data has found plausible evidence that the
been done, a study of older adults with either depression SNCA gene is involved in the shared genetic vulnerability
or dysthymia has found evidence of abnormal dopamine for PD and AlzD [103] , and recent evidence has implicated the
transporter binding on single-photon emission computed SNCA gene in the pathogenesis of depressive disorders .
[59]
tomography (SPECT), and these alterations are associated Although a definitive causal association cannot be
with prodromal features of PD . In a similar imaging established through the current results, they do provide
[99]
study comparing patients with MDD alone and those with some support to the growing body of evidence implicating
MDD superimposed on dysthymia (double depression), α-synuclein in the pathophysiology of depression [47-49] and
ligand binding to striatal dopamine transporters was found AlzD [16,104,105] . The links between SNCA and both PD and
to be inversely correlated with illness duration only in the AlzD were not significant after correcting for the prevalence
double depression group [100] . These findings, although few of MDD; however, they remained significant after adjusting
in number, are consistent with the possibility of a shared for dysthymia. When taken in conjunction with the results
“hypodopaminergic” phenotype, characterized by specific of direct bivariate correlations between SNCA distributions
neuropsychological deficits, that can be identified in and depression, the following tentative interpretation can
patients with depressive disorders, AlzD, and PD . It is be advanced: certain functional polymorphisms of SNCA
[80]
possible that some cases of dysthymia may reflect an early may be a shared risk factor for MDD, PD, and AlzD,
or prodromal stage of neurodegenerative disorders linked and they may interact with dysthymia to influence the
to dopaminergic deficit. This possibility is also supported subsequent risk of both neurological disorders. Although it
[17]
by the overlap between some of the core symptoms of is intriguing and consistent with recent clinical evidence ,
dysthymia, such as fatigue and apathy, and the non-motor this association is purely ecological in nature and requires
symptoms of PD [101] . When adjusting for PM2.5 levels and careful evaluation in clinical and community samples.
pesticide exposure in the present study, the relationship The analysis of gene-environment interactions based
between dysthymia and both PD and AlzD remained on ecological data has certain shortcomings, and such
significant. This suggests that depressive disorders and results should be interpreted with caution [106] . Therefore,
environmental toxins may independently influence the these analyses were considered a secondary objective in
risk of neurodegenerative disorders, similar to what earlier the current study. After taking air pollution and pesticide
studies have discovered [102] . exposure into account, two of the studied polymorphisms
When examining the relationship between the allele (rs356220 and rs2736990) were no longer associated with
frequencies of specific SNCA SNPs in the current study, it either PD or AlzD, suggesting that if these genes do truly
was found that the distributions of all three SNPs (rs356220, represent vulnerability factors for either disorder, they do so
rs2736990, and rs3775439) were significantly correlated only in association with exposure to environmental toxins.
with the prevalence of depression, PD, and AlzD at both However, this was not observed in the case of rs3775439,
time points (Table 4). With the exception of dysthymia thus suggesting the absence of such an interaction (Table 4).
in 2019, the strengths of the observed correlations were An earlier case-control study of patients with PD has found
almost identical in 1990 and 2019, which is consistent that the gene-environment interaction between exposure
with the relatively “fixed” effect that would be expected to ambient nitrogen dioxide (NO ) and the functional
2
from specific vulnerability loci. After adjustment for polymorphism of IL1β gene is significant associated with
[107]
confounding factors, the rs3775439 A→G polymorphism the risk of PD . It is possible that similar effects may
remained significantly associated with depression, PD, and occur in the case of SNCA gene variations, but this cannot
AlzD. These results should be interpreted with caution in be conclusively deduced from the current results.
view of the minimal number of countries for which data Certain key limitations of the current study should
were available (n = 18–32). However, they are consistent be borne in mind. First, as the study was based on
with the hypothesis of a shared genetic vulnerability for cross-national estimates, there may be a certain level of

Volume 2 Issue 1 (2023) 8 https://doi.org/10.36922/an.326