Sex-Dependent Dynamics of Behavioural and Neuropathological Changes in an A53T Alpha-Synuclein Mouse Model of Parkinson’s Disease

TL;DR

This study shows that male mice are more vulnerable to early motor and brain changes caused by a Parkinson’s-related protein, highlighting the importance of sex in understanding the disease.

Contribution

The study reveals sex-dependent differences in early neuropathological and behavioral changes in a Parkinson’s disease mouse model.

Findings

Male mice showed early subtle motor deficits and increased immobility compared to females.

Males exhibited faster progression of striatal axonopathy, while both sexes showed increased astrogliosis.

Neuronal loss in the substantia nigra compacta was not observed early, suggesting axonal degeneration precedes it.

Abstract

Parkinson’s disease (PD) is characterised by progressive dopaminergic neurodegeneration, alpha-synuclein (α-syn) aggregation, and neuroinflammation. Clinical and experimental studies suggest that sex influences disease onset, progression, and treatment response, yet its impact on α-syn-mediated pathology remains incompletely understood. In this study, we investigated sex-dependent progression of behavioural and neuropathological alterations in a mouse model overexpressing A53T α-syn. Male and female C57BL/6J mice received bilateral intranigral injections of adeno-associated viral vectors encoding mutant A53T α-syn or empty vectors. Motor performance was assessed at 60 and 120 days post-surgery using open field, wire hang, pole, and balance beam tasks complemented by automated behavioural analysis (DeepLabCut, SimBA). Brains were processed for immunohistochemical evaluation of α-syn accumulation, tyrosine hydroxylase (TH) expression, axonal integrity, and glial activation. A53T α-syn overexpression induced early subtle motor deficits primarily in males, accompanied by increased immobility on the balance beam despite preserved substantia nigra compacta neuron counts. By 120 days, striatal TH immunoreactivity was markedly reduced in α-syn mice. An integrated axonal degeneration index, combining TH optical density and swelling counts, revealed a faster progression of striatal axonopathy in males. Both sexes showed enhanced striatal astrogliosis, indicating α-syn-driven neuroinflammation independent of sex. These findings identify early axonal degeneration and reactive astrogliosis as key pathological events preceding neuronal loss in A53T α-syn mice. Importantly, the pronounced male vulnerability highlights sex as a critical biological variable in modelling PD progression and in developing precision-based neuroprotective strategies.

The online version contains supplementary material available at 10.1007/s10571-026-01707-9.

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