INVESTIGATING SIAH2-E3 LIGASE ACTIVATION AND MITOCHONDRIAL DYSFUNCTION IN FAMILIAL AND SPORADIC MODELS OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by α-synuclein (αSyn) aggregation and mitochondrial dysfunction, features shared by both familial and sporadic forms. Although the molecular mechanisms underlying dopaminergic neurodegeneration remain debated, evidence indicate that the E3 ubiquitin ligase Seven in Absentia Homolog 2 (Siah2) interacts with αSyn and mitochondrial proteins, suggesting its involvement in PD pathogenesis.
This study focuses on the role of Siah2 in mitochondrial dynamics and αSyn aggregation in in vitro and ex vivo models of PD. To this aim, experiments were performed in SH-SY5Y cells treated with rotenone for 24 hours to mimic the sporadic form of PD and in A53T transgenic mice, representing the familial form of the disease.
In rotenone-treated SH-SY5Y cells, Siah2 protein expression increased along with LC3-II, an autophagy marker, whereas TFAM, a mitochondrial biogenesis marker, decreased. Additionally, co-immunoprecipitation assay demonstrated an interaction between Siah2 and PINK1, a key regulator of mitophagy. Confocal microscopy confirmed that these alterations were associated with changes in mitochondrial membrane potential and calcium levels.
Ex vivo experiments further supported this hypothesis. Indeed, upregulation of Siah2 and LC3-II was detected in the midbrain and striatum of 4- and 12- month-old A53T transgenic mice, accompanied by increased accumulation of pS129-αSyn. Immunofluorescence and co-immunoprecipitation experiments revealed a co-localization between Siah2 and pS129-αSyn in neurons of the above mentioned brain regions.
In conclusion, these results let to hypothesize a role of Siah2 in mitophagy regulation and mitochondrial functional impairment in both PD models by interacting with mitochondrial proteins and αSyn.