Parkinson's disease etiology
It is clear that the immune system and inflammation have a role in Parkinson's disease (PD), including sporadic Parkinson's disease and some genetic forms such as LRRK2-associated Parkinson's disease. One of the most important genes associated with PD is GBA1, as mutations in this gene are found in 5-20% of PD patients in different populations worldwide. Biallelic mutations in GBA1 may cause Gaucher disease, a lysosomal storage disorder with involvement of the immune system, and other lines of evidence link GBA1 to the immune system and inflammation 1).
The cause of PD is unknown in most cases. Genetic risk factors have been identified, including monogenetic causes that are rare in unselected populations. Some genetic factor can be identified in 5-10% of the patients 2)
Epigenetic influences mediating brain iron deposition, oxidative mitochondrial injury, and macroautophagy in Parkinson's disease and related conditions remain enigmatic 3).
Sporadic PD is hypothesized to be a result of genetic susceptibility interacting with environmental insult. Epidemiological studies suggest that pesticide exposure is linked to higher PD risk, but there are no studies demonstrating SN changes with chronic pesticide exposure in human subjects.
The changes detected by MRI may mark “one of the hits” leading to PD, and underlie the increased risk of PD in pesticide users found in epidemiological studies. Further human studies assisted by these imaging markers may be useful in understanding the etiology of PD 4).
Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD 5).
Over the years Genome-wide association study (GWAS) have identified numerous genetic risk factors, however it is unclear whether genetics contribute to disease Parkinson's disease etiology in a sex-specific manner.
A study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females 6).