Sex and Age Differences in a Progressive Synucleinopathy Mouse Model.

Area of Science:

• Neuroscience
• Genetics
• Endocrinology

Background:

• Alpha-synuclein (αSyn) protein mutation and overexpression cause synucleinopathies, linked to Parkinson's disease (PD).
• Men exhibit higher PD prevalence than women, suggesting hormonal influences on PD progression.
• Rodent male nigrostriatal dopamine (DA) neurons are more susceptible to toxins than females.

Purpose of the Study:

• To investigate the impact of biological sex on synucleinopathy.
• To compare αSyn toxicity in male and female mice with αSyn knockout and overexpression.

Main Methods:

• Utilized mice models: wildtype (WT), murine αSyn knockout (SNCA-/-), and human αSyn overexpressing (SNCA-OVX).
• Assessed behavioral changes (locomotor activity, anxiety), αSyn accumulation, nigrostriatal DA neuron loss, striatal DA content, neuroinflammation (astrogliosis, microgliosis), and cytokine levels with age.
• Compared outcomes between sexes in SNCA-OVX and WT mice.

Main Results:

• Both SNCA-/- and SNCA-OVX mice displayed age-dependent behavioral deficits.
• Male SNCA-OVX mice showed accelerated locomotor decline and nigrostriatal DA loss compared to females.
• Human αSyn overexpression, but not knockout, was toxic to DA neurons, with neuroprotection diminishing in females by 18 months.

Conclusions:

• Biological sex significantly influences αSyn toxicity and PD-like pathology.
• Male mice exhibit exacerbated synucleinopathy progression and DA neurodegeneration.
• Estrogen's potential neuroprotective role may be lost with aging or reproductive cycle changes in females.