Sex and Age Differences in a Progressive Synucleinopathy Mouse Model

The mutation and overexpression of the alpha-synuclein protein (& alpha;Syn), described as synucleinopathy, is associated with Parkinson's disease (PD)-like pathologies. A higher prevalence of PD is documented for men versus women, suggesting female hormones' implication in slowing PD progression. The nigrostriatal dopamine (DA) neurons in rodent males are more vulnerable to toxins than those in females. The effect of biological sex on synucleinopathy remains poorly described and was investigated using mice knocked out for murine & alpha;Syn (SNCA-/-) and also overexpressing human & alpha;Syn (SNCA-OVX) compared to wildtype (WT) mice. All the mice showed decreased locomotor activity with age, and more abruptly in the male than in the female SNCA-OVX mice; anxiety-like behavior increased with age. The SNCA-OVX mice had an age-dependent accumulation of & alpha;Syn. Older age was associated with the loss of nigral DA neurons and decreased striatal DA contents. The astrogliosis, microgliosis, and cytokine concentrations increased with aging. More abrupt nigrostriatal DA decreases and increased microgliosis were observed in the male SNCA-OVX mice. Human & alpha;Syn overexpression and murine & alpha;Syn knockout resulted in behavioral dysfunctions, while only human & alpha;Syn overexpression was toxic to DA neurons. At 18 months, neuroprotection was lost in the female SNCA-OVX mice, with a likely loss of estrus cycles. In conclusion, sex-dependent & alpha;Syn toxicity was observed, affecting the male mice more significantly.

Automated summary

The mutation and overexpression of alpha-synuclein protein is associated with Parkinson's disease. The prevalence of PD is higher in men than in women, suggesting the involvement of female hormones in slowing PD progression. In mice, male individuals are more vulnerable to toxins and exhibit more severe toxicity from alpha-synuclein protein than females.