Objective: Develop a potential disease-modifying gene therapy for men with Parkinson’s Disease

Background: A hallmark symptom of PD is the loss of midbrain dopamine (DA) neurons which control voluntary movement. There is no cure for PD nor drugs to stop or reverse the neurodegeneration. While the mechanism of DA cell loss in PD is unknown, male sex is a strong risk factor. PD affects twice as many men as women, has an earlier age of onset, and steeper rate of disease progression. Previously we showed in rats that the sex determining Y-chromosome gene product, SRY, regulates adult brain function only in males[1]. We hypothesized that SRY contributes to male bias in PD.

Method: In vitro PD model: Male human neuroblastoma cell line M17 was cultured with PD toxins, 6-hydroxydopamine or rotenone.
In vivo PD model: Hemi-Parkinsonism model was created by cannulating the rat on one side above the substantia nigra and introducing these two dopamine toxins. Repeated Sry antisense oligonucleotides (ASOs) infusions to knockdown SRY. Motor behaviours, histological and molecular analyses were undertaken.

Results: We found abnormally high levels of Sry in both in vitro and in vivo toxin models of experimental PD. PD toxin treatment of human male neuroblastoma M17 cells led to a 5-fold upregulation of SRY[2]. In 6-hydroxydopamine and rotenone rat models of PD, Sry levels in the midbrain were elevated 3-4 fold[3]. We investigated whether this aberrant SRY overexpression is deleterious. To suppress SRY expression, ASOs were designed against rat Sry mRNA. Remarkably, lowering nigral Sry expression in male PD rats to near physiological levels prevented nigral cell loss and motor symptoms from worsening in both models[3]. The protective effect of the SRY ASOs was associated with male-specific reductions in nigrostriatal neuron degeneration, mitochondrial degradation, DNA damage, and neuroinflammation[3].

Conclusion: Upregulation of SRY during neuron injury is deleterious and contributes to male susceptibility at least in PD models. Therefore, suppressing nigral SRY synthesis represents a sex-specific strategy to protect DA cells from death, and could be a new potential clinically therapeutic mechanism for men with PD. However, SRY gene sequences differ considerably between animal species. In current we are designing stable humanised 2-O-Methoxyethyl based versions of SRY ASOs in vitro toward a stable and efficacy humanised SRY ASOs.

References: [1] Dewing P, et al. (2006) Curr. Biol 16: 415-420. [2] Czech DP, et al. (2014) Endocrinology 155: 2602-12. [3] Lee J, et al. (2019) PNAS 116: 16577-16582.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sry-as-a-potential-therapeutic-target-for-men-with-parkinsons-disease/