Objective: We investigated the relationship between alternative autophagy and VPS35 D620N mutant-related PD pathogenesis.

Background: VPS35 is critically involved in the mechanisms of neurodegeneration observed in Alzheimer’s and Parkinson’s diseases (PD). Numerous genetic studies have established a strong link between autophagy and the pathology of PD, particularly highlighting the role of the PD-related D620N mutation in VPS35, which disrupts autophagy. The exact molecular processes responsible for neuronal cell death and the disruption of autophagy in PD remain a subject of ongoing debate. Importantly, there is growing evidence to support the contribution of Rab9-mediated “alternative” autophagy, governed by a distinct molecular mechanism from the one driving ATG5-dependent “conventional” autophagy, to the neurodegenerative process.

Method: We isolated iPSCs from the blood mononuclear cell population of two PD patients carrying the VPS35 D620N mutant. In addition, we used CRISPR-Cas9 to generate SH-SY5Y cells carrying the D620N variant of VPS35.

Results: Our initial findings show a notable reduction in autophagic vacuoles in both ATG5-deficient Mouse Embryonic Fibroblasts and patient-derived dopaminergic neurons with the VPS35 D620N mutation, compared to cells with normal VPS35. Additionally, estrogen, known to trigger alternative autophagy pathways, was observed to increase the autophagic vacuole count in ATG5-suppressed dopaminergic neurons harboring the VPS35 D620N mutation. Estrogen achieves this by inducing Rab9 phosphorylation via Ulk1 phosphorylation, thereby facilitating alternative autophagy. Moreover, estrogen notably decreased the apoptosis rate in neurons with the VPS35 D620N mutation, an effect that was less pronounced when alternative autophagy pathways were inhibited.

Conclusion: Alternative autophagy might be important for maintaining neuronal homeostasis and may be associated with the neuroprotective effect of estrogen in PD with VPS35 D620N.

References: Shiraishi T, et al. The impact of VPS35 D620N mutation on alternative autophagy and its reversal by estrogen in Parkinson’s disease. Cellular and Molecular Life Sciences. 2024.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-impact-of-vps35-d620n-mutation-on-alternative-autophagy-and-its-reversal-by-estrogen-in-parkinsons-disease/