Inclusion of a portion of the native SNCA 3′UTR reduces toxicity of human S129A SNCA on striatal‐projecting dopamine neurons in rat substantia Nigra

Abstract

Experimental models of Parkinson’s disease (PD) created by aberrant expression of the alpha-synuclein (SNCA) coding region have been reported. However, non-coding regions function in normal physiology and recent in vitro studies have shown that microRNAs-7 and -153 regulate SNCA expression by binding the 3′UTR. Here, effects of different hSNCA forms were examined in vivo. Adult, male rats were injected into one substantia nigra (SN) with AAV-wtSNCA, AAV-S129A hSNCA, or AAV-S129DhSNCA either with or without a portion of the native 3′UTR. DA neurons in SN that maintained striatal (ST) projections at the end of treatment were retrogradely labeled by bilateral ST fluorogold (FG) injections and FG-positive DA neurons in SN were counted. At 5wks, hSNCA coding vectors reduced numbers of FG-positive neurons in injected SN compared to uninjected SN (wtSNCA, p≤0.05; S129A/D hSNCA, p≤0.01). At 7 and 9wks, wtSNCA- and S129D hSNCA-treated rats exhibited recovery, but S129A hSNCA-injected rats did not (p≤0.01). In contrast, numbers of FG-positive neurons were unaffected by hSNCA expression when the 3′UTR was included. When FG-positive neurons were expressed as the ratio of numbers in injected to uninjected sides, the S129AhSNCA coding vector resulted in the highest decrease at 9wks versus wtSNCA (p≤0.05) or S129D hSNCA (p≤0.01). Inclusion of the 3′UTR resulted in no significant differences in FG-positive neuron ratios. These data suggest that inclusion of the 3′UTR protects against S129A hSNCA-induced loss of nigrostriatal-projecting DA neurons in vivo and that mis-regulation of hSNCA expression and function at non-coding regions contribute to PD pathogenesis.

Unravelling Endogenous MicroRNA System Dysfunction as a New Pathophysiological Mechanism in Machado-Joseph Disease

“…These results are in accordance with the report that the regulation of human alpha-synuclein at its 3 0 UTR also decreases its levels and toxicity in vivo. 54 Interestingly, overexpression of mutATXN3-3 0 UTR in vivo resulted in remarkably low toxicity. Notably, this finding is in accordance with the previously mentioned MJD transgenic mouse models that include the 3 0 UTR of ATXN3.…”

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

“…This phosphorylation is also found in pre‐LB stages suggesting that it is strongly associated to disease progression (Saito et al., ). The pharmacological modulation of this phosphorylation may be a relevant strategy for slowing PD progression, although several studies show α‐syn‐related toxicity is enhanced when the Ser129 residue is mutated to an unphosphorylatable alanine residue (Da Silveira et al., ; Gorbatyuk et al., ; Khodr, Pedapati, Han, & Bohn, ). Some kinase interactors have been identified that can modulate Ser129 phosphorylation including polo‐like kinases, casein kinases, and G protein‐coupled receptor kinase (Inglis et al., ; Ishii et al., ; Pronin, Morris, Surguchov, & Benovic, ).…”

Cell-Specific Post-Transcriptional Regulation of γ-Synuclein Gene by Micro-RNAs

“…This type of regulation plays an essential role in the transition of normal to pathogenic functions of α-synuclein [24]–[28]. At least two miRs, miR-7 and miR-153 are involved in 3′-UTR mediated negative control of α-synuclein expression [27]–[30]. Furthermore, miR-133b is deficient in the Parkinson’s disease midbrain, and miR-34b/34c is decreased in certain brain regions in patients [24].…”