Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson's disease

Joohyung Lee, Paulo Pinares-Garcia, Hannah Loke, Seungmin Ham, Eric Vilain, Vincent Harley

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder caused by the loss of midbrain dopamine (DA) neurons. While the cause of DA cell loss in PD is unknown, 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. Here we demonstrate that nigral SRY expression is highly and persistently up-regulated in animal and human cell culture models of PD. Remarkably, lowering nigral SRY expression with antisense oligonucleotides in male rats diminished motor deficits and nigral DA cell loss in 6-hydroxydopamine (6-OHDA)-induced and rotenoneinduced rat models of PD. The protective effect of the SRY antisense oligonucleotides was associated with male-specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin-induced rat models of PD. Moreover, reducing nigral SRY expression diminished or removed the male bias in nigrostriatal degeneration, mitochondrial degradation, DNA damage, and neuroinflammation in the 6-OHDA rat model of PD, suggesting that SRY directly contributes to the sex differences in PD. These findings demonstrate that SRY directs a previously unrecognized malespecific 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.

Original languageEnglish
Pages (from-to)16577-16582
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number33
DOIs
Publication statusPublished - 13 Aug 2019

Keywords

  • Brain sex differences
  • Inflammation
  • Neuroprotection
  • Sex chromosome
  • Transcription factor

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