Modulation of Alpha-synuclein Expression and Associated Effects by MicroRNA Let-7 in Transgenic C. elegans

Abstract

Neurodegenerative Parkinson’s disease (PD) is a multi-factorial disorder lacking complete cure. Understanding the complete mechanism of initiation and progression of this disease has been quite challenging; however, progress has been made toward deciphering certain genetic aspects related to the disease condition. Genetics studies have provided clues toward the role of microRNAs (miRNAs) in various disease conditions. One of the crucial miRNA molecules, let-7, is highly conserved miRNA and is known to regulate important functions of development and viability; its altered expression has been reported in C. elegans model of PD. We carried out studies with let-7, employing transgenic C. elegans model expressing ‘human’ alpha-synuclein and developed a let-7 loss-of-function model toward studying the downstream effects related to PD. We observed that let-7 miRNA was upregulated in C. elegans model of PD and figured that loss of let-7 miRNA leads to decreased alpha-synuclein expression, increased autophagy, increased Daf-16 expression, increased oxidative stress and increased lipid content with no effect on dopaminergic/acetylcholinergic neurons. Our findings indicate that let-7 miRNA regulates PD-associated pathways. Our study provides insight toward the role of let-7 in regulating expression of genes associated with these pathways which might have implications on the multi-factorial nature of PD. Potential pharmacological agents modulating the expression of let-7 could be studied toward targeting the multi-factorial aspect of PD.

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

“…Inhibition of let-7 protected cells from apoptosis by reducing two pro-apoptotic genes, ced-4 and jnk-1. Altogether, these results highlight let-7 as a promising miRNA target for PD therapeutics that act against multiple underlying mechanisms of the disease [87].…”

“…Finally, three other microRNAs are involved in α-Syn regulation, exerting a direct regulation by binding to its 3'-UTR region (miR-214), or an indirect effect, as occurs for Let-7 and miR-16-1 [41,43,87].…”

“…Let-7 regulates α-Syn via the autophagy-lysosome network, a pathway that executes α-Syn clearance under physiological conditions [87][88][89][90]. In a Caenorhabditis elegans model of PD, depletion of let-7 led to α-Syn accumulation.…”

“…In a Caenorhabditis elegans model of PD, depletion of let-7 led to α-Syn accumulation. The change was related to increased levels of lgg-1 and atg-13 and consequent degradation of cellular components and autophagy-related genes, respectively [87,[91][92][93]. miR-16-1 has several binding sites in the 3 -UTR region of HSP70.…”

“…Finally, the microRNA Let-7 also plays a role in α-Syn regulation, affecting an autophagy-lysosome pathway that executes the clearance of α-Syn in healthy cells [87]. The role of let-7 in α-Syn accumulation was studied in a transgenic C. elegans model of PD that expresses human α-Syn.…”