Sex-specific vulnerability to behavioural and morphological alterations in a mouse model of Parkinson's disease overexpressing mutant A53T alpha-synuclein

Parkinsons disease (PD) is characterised by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and accumulation of misfolded -synuclein (-syn). Neuroinflammation also contributes to disease onset and progression. Notably, PD exhibits sexual dimorphism in clinical presentation and treatment response. This study investigated sex-specific behavioural and morphological changes in a mouse model overexpressing A53T -syn. Male and female C57BL/6J mice received bilateral intranigral injections of adeno-associated viral vectors encoding mutant A53T -syn or empty vectors. Motor function was assessed at 60 and 120 days post-surgery using open field, wire hang, pole, and balance beam tests. Brains were collected for immunohistochemical analyses of -syn pathology, nigrostriatal integrity (tyrosine hydroxylase, TH), axonal degeneration, and neuroinflammation. -Syn overexpression induced early, subtle motor deficits primarily in males, despite preserved SNc neuronal density. Automated analysis of balance beam walking behaviour (DeepLabCut, SimBA) revealed increased immobility and reduced walking time in -syn males. At 120 days only, striatal TH levels were significantly reduced, driven by reductions in -syn males. Although undetected at 60 days, an axonal degeneration index (combining striatal TH optical density and axonal swellings) revealed more advanced degeneration in -syn males, suggesting faster disease progression. At both time points, -syn mice showed increased striatal astrogliosis without sex differences, indicating -syn-associated neuroinflammation. These findings support a PD model of early axonal degeneration and reactive astrogliosis preceding neuronal loss. The sex-specific behavioural and neuropathological patterns underscore the importance of incorporating sex as a biological variable in preclinical models and developing tailored therapeutic strategies.