Objective: Given the presence and function of SRY in male DA (dopamine) neurons, we hypothesised that dysregulation of SRY may contribute to male susceptibility to PD (Parkinson’s disease).

Background: PD is a debilitating neurodegenerative disorder caused by the loss of midbrain DA neurons. Male sex is a strong risk factor. Aside from the protective actions of sex hormones in females, emerging evidence suggests that sex-chromosome genes contribute to the male bias in PD. We previously showed that the Y-chromosome gene, SRY, directly regulates adult brain function in males independent of gonadal hormone influence. SRY protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement.

Method: Human cell culture and toxin-induced rat models of PD were combined with repeated Sry antisense oligonucleotide (ASO) infusion. Motor behaviours, histological and molecular analyses were undertaken.

Results: Nigral SRY expression is highly and persistently up-regulated in animal and human cell culture models of PD. Lowering nigral SRY expression with ASO in male rats diminished motor deficits and nigral DA cell loss in toxin-induced rat models of PD. The protective effect of the Sry ASO was associated with male-specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin-induced rat models of PD [1]. New data addressing the mechanism of oligodeoxynucleotide induced neuroprotection by SRY will be discussed.

Conclusion: SRY directs a previously unrecognized male-specific mechanism of DA cell death and suggests that suppressing nigral Sry synthesis represents a sex-specific strategy to slow or prevent DA cell loss in PD.

References: [1] Lee J, Pinares-Garcia P, Loke H, Ham S, Vilain E, Harley VR (2019). Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson’s disease. PNAS, 116(33), 16577-16583. doi: 10.1073/pnas.1900406116.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-specific-neuroprotection-by-inhibition-of-the-y-chromosome-gene-sry-in-experimental-parkinsons-disease/