The role of retroelements in Parkinson’s disease development

TL;DR

This paper explores how retroelements, like LINE1s and Alu elements, may contribute to Parkinson’s disease by affecting alpha-synuclein accumulation and inflammation in the brain.

Contribution

The paper introduces a novel hypothesis linking retroelement activation with Parkinson’s disease progression through antiviral response and microRNA mechanisms.

Findings

Alpha-synuclein aggregates in Parkinson’s disease may result from interactions with retroelement transcripts.

Activation of LINE1s and Alu elements in Parkinson’s patients is linked to mitochondrial dysfunction and neurodegeneration.

35 microRNAs derived from retroelements are identified as potential therapeutic targets for Parkinson’s disease.

Abstract

Parkinson’s disease is the second most common neurodegenerative disease characterized by accumulation of alpha-synuclein and Lewy bodies in the brain’s substantia nigra. Genetic studies indicate an association of various SNPs, many of which are located in intergenic and intronic regions, where retrotransposons and non-coding RNA genes derived from them reside, with this disease. Therefore, we hypothesize the influence of SNPs in retroelement genes on Parkinson’s disease development. A susceptibility factor is retrotransposons activation with age, since the disease is associated with aging. We hypothesized that alpha-synuclein accumulates in the brain due to its interaction with transcripts of activated retroelements. As a result of a defective antiviral response and a large number of RNA targets for this protein, its aggregates form Lewy bodies in neurons with inflammation and neurodegeneration development in the substantia nigra. As evidence, data are presented on the role of alpha-synuclein in the antiviral response with binding to RNA viruses, which are characterized by the ability to activate retroelements that have evolved from exogenous viruses integrated into the human genome. Activation of LINE1s in the brain, endogenous retroviruses, and LINE1s in the blood serum of Parkinson’s disease patients was detected. An additional mechanism contributing to the progression of the disease is mitochondrial dysfunction due to insertions of Alu elements into their genomes using LINE1 enzymes. Mechanisms of activated retrotransposons’ influence on microRNAs that evolved from them are described. Analysis of the scientific literature allowed us to identify 35 such microRNAs (miR-1246, -1249, -1271, -1273, -1303, -151, -211, -28, -31, -320b, -320d, -330, -335, - 342, -374a, -374b, -421, -4293, -4317, -450b, -466, -487b, -493, -495, -5095, -520d, -576, -585, -6088, -619, -625, -626, -769, -885, -95) associated with Parkinson’s disease, which may become promising targets for its treatment and diagnosis.

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