Wednesday, February 5, 2025
2/5/2025
Project Summary Parkinson’s disease (PD) is a common age-related neurodegenerative disorder characterized by loss of dopaminergic (DA) neurons in the midbrain. A hallmark of both familial and sporadic PD is the presence of Lewy body inclusions consisting of aggregated forms of the protein alpha-synuclein (a-syn), which is encoded by the SNCA gene. Recent work by our lab has supported a large body of literature demonstrating that a-syn accumulation disrupts protein homeostasis in neuronal models of PD. In neurons differentiated from induced pluripotent stem cells (iPSCs) from patients harboring mutations in SNCA, we observed impaired autophagic clearance of misfolded proteins, ER morphology changes, and deficits in lysosomal hydrolase tracking. These deficits in the autophagy-lysosomal pathway (ALP) are intriguing given that GWAS studies have identified variants in several genes encoding for ALP proteins that modify risk for developing PD. For instance, variants in the gene GBA1, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase), are the greatest genetic risk factor for developing PD and Dementia with Lewy Bodies (DLB). Previous work from our lab has shown that wild-type GCase accumulates in the ER of SNCA triplication mutation neurons, accompanied by dramatic ER fragmentation. Yet, despite an increase in ER stress in these cells, the unfolded protein response (UPR) fails to activate and either refold or degrade accumulating unstable ER proteins, including insoluble GCase. Intriguingly, unbiased mass spectrometry revealed that several proteins involved in the selective autophagic degradation of the ER, or ER-phagy, are significantly depleted in SNCA triplication neurons relative to isogenic controls, suggesting that ER-phagy may be dysregulated in these cells. As ER-phagy plays an important role in ER protein homeostasis and ER membrane remodeling, this hypothesis is consistent with the observations of ER- fragmentation and insoluble protein accumulation observed in SNCA triplication neurons. While there is strong genetic and pathological evidence implicating a-syn and the ALP in PD pathogenesis and a-syn-induced disruptions to ER homeostasis and autophagy, relatively little is known about the role of ER-phagy in PD. Here, we intend to resolve some key questions regarding a potential role of ER-phagy in PD pathogenesis. In Aim 1, we will measure ER-phagy flux in SNCA triplication neurons and isogenic controls to determine whether a-syn accumulation impairs ER-phagy and delineate the means through which this impairment may occur. In aim 2, we will investigate the mechanism of wild-type GCase accumulation in the ER of SNCA triplication neurons, and if enhancement of ER-phagy can restore ER homeostasis through alleviating accumulated GCase. As a-syn accumulation is common across PD and DLB, and ER proteostasis defects are commonly observed across neurodegenerative diseases, by resolving these questions, we hope to uncover insights that hold broad therapeutic potential.
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