Upregulation of α-synuclein following immune activation: Possible trigger of Parkinson's disease

Alpha-synuclein (alpha-syn) has been suggested to have many functions including, vesicle transport in neurons, transcriptional regulator, modulator of immune cell maturation and response, and a role as an antimicrobial peptide.This protein forms insoluble aggregates, called Lewy bodies, in several neurodegenerative diseases, termed synucleinopathies, including Parkinson's disease (PD), Multiple System Atrophy, and Lewy Body Dementia, and aggregates are also commonly found in Alzheimer's disease. Moreover, multiplications and point mutations in the gene cause rare autosomal dominant forms of parkinsonism, which resemble sporadic PD. It has been suggested that the accumulation of alpha-syn in the monomeric state followed by aggregation of the protein and seeding of further pathogenic alpha-syn aggregates are key steps in the pathogenesis of synucleinopathies. The triggers of alpha-syn aggregation in neurodegeneration are unknown, but inflammation caused by bacterial and viral pathogens or exposure to environmental toxins have been implicated. The purpose of this review is to present emerging evidence that alpha-syn may play a role in the immune response to pathogens. We present recent findings suggesting that upregulation of alpha-syn levels is a normal response to infections. We propose that under certain conditions (e.g., dysregulated inflammatory responses due to genetic predisposition and aging), monomeric alpha-syn will form oligomers that are taken up by nerve endings and undergo axonal transport to the central nervous system, where they can aggregate into pathogenic fibrils. Under unfavorable conditions, we suggest that this process can trigger neurodegenerative disease. Therefore, a deeper understanding of the roles of alpha-syn in the immune system could provide crucial insights into the origins of synucleinopathies.

Automated summary

Alpha-synuclein plays multiple roles in neurons and is involved in the pathogenesis of synucleinopathies. Recent evidence suggests its potential involvement in the immune response, and under certain conditions, its aggregation may trigger neurodegenerative diseases.