Degradation of alpha-synuclein/SNCA mRNA by RNautophagy

α-Synuclein is a neuronal protein and main component of Lewy bodies, the pathological hallmark of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. While the accumulation of α-synuclein in neurons is implicated in the pathogenesis of these disorders, the mechanisms underlying α-synuclein mRNA degradation remain poorly understood. RNautophagy is a lysosomal RNA degradation pathway in which RNA is directly taken up into lysosomes and subsequently degraded. SIDT2, a lysosomal membrane protein, mediates the uptake of RNA. In this study, we investigated whether SIDT2-mediated RNautophagy degrades α-synuclein mRNA. Knockdown of SIDT2 led to reduced degradation of α-synuclein mRNA, whereas overexpression of wild-type SIDT2 enhanced its degradation, suggesting its role in α-synuclein mRNA turnover. In contrast, overexpression of the RNA uptake-deficient S564A mutant did not enhance degradation, indicating that RNA uptake activity is required for SIDT2-mediated degradation of α-synuclein mRNA. Using a series of deletion mutants, we identified a guanine (G)-rich sequence within the 5' untranslated region (5'-UTR) of α-synuclein mRNA as a key determinant of SIDT2-dependent degradation. Furthermore, insertion of the G-rich sequence into the 5'-UTR of GFP mRNA promoted SIDT2-dependent degradation of GFP mRNA and reduced GFP protein expression. Taken together, these results indicate that SIDT2-mediated RNautophagy contributes to the degradation of α-synuclein mRNA via the G-rich region within the 5'-UTR. Our findings may also provide insights into the pathogenesis of Lewy body diseases.