SNCA (α-synuclein) H50Q mutation reveals distinct neurodegenerative patterns and adaptive responses in Parkinson's disease Drosophila model.

Parkinson's disease (PD) is defined by the progressive degeneration of midbrain dopaminergic neurons, a process closely linked to α-synuclein aggregation. Paradoxically, although the SNCA^H50Q mutation is associated with delayed-onset familial PD in humans, it enhances α-synuclein aggregation and cytotoxicity in vitro, highlighting the need to elucidate the molecular mechanisms that modulate disease progression. In this study, we employed Drosophila melanogaster as an in vivo model to investigate wild-type (SNCA^WT) and mutant (SNCA^H50Q)-mediated neurotoxicity during PD progression. A comprehensive series of behavioural, biochemical, and neuroanatomical analyses was performed. Climbing and locomotion tracing assays across ageing cohorts (days 10, 20, and 30) revealed progressive motor dysfunction in SNCA^WT flies, accompanied by an increased centrophobism index indicative of postural instability and bradykinesia. SNCA^H50Q flies exhibited pronounced late-stage bradykinesia, marked by reduced distance travelled and diminished motor output at 30 days of age. Qualitative histological assessment and scanning electron microscopy (SEM) analysis of paraffin brain sections and eyes, respectively, revealed morphological alterations in SNCA^H50Q flies. Biochemical profiling demonstrated a compensatory antioxidant response in SNCA^WT flies, whereas SNCA^H50Q flies exhibited reduced catalase activity, indicative of enhanced oxidative stress. In a combined genetic and rotenone-induced PD model, SNCA^H50Q flies displayed improved survival, suggesting engagement of adaptive stress-responsive mechanisms. Collectively, these mutation-specific phenotypes underscore the importance of in vivo models in delineating adaptive mechanisms that modulate disease onset and progression.