Chen Chase, Ma Charis, Sam Richard, Lichtenberg Jens, Chen Tiffany, Hao Ying, Li Ziyi, Kowal Isabelle, Andersh Kate, Qi Yue Andy, Perez Gani, Hertz Ellen, Li Yan, Williams Darian, Henderson Mark J, Park Morgan, Jiang Xuntian, Jerez Pilar Alvarez, Blauwendraat Cornelis, Sidransky Ellen, Chen Yu
Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815.
bioRxiv. 2025 Jun 25:2025.06.23.661126. doi: 10.1101/2025.06.23.661126.
Variants in are common genetic risk factors for several synucleinopathies. The increased risk has been attributed to the toxic effects of misfolded glucocerebrosidase (GCase) (gain-of-function), and the accumulation of lipid substrates due to reduced enzyme activity (loss-of-function). To delineate pathogenicity, an iPSC line was generated from a patient with both type 1 Gaucher disease (: N370S/N370S; p.N409S/p.N409S) and Parkinson disease (PD). From this line, we created a reverted wild-type (WT) line and a knockout (KO) line to eliminate misfolded GCase and intensify lipid accumulation. N370S/N370S and KO dopaminergic neurons (DANs) exhibited decreasing GCase levels and progressive accumulation of lipid substrates compared to WT DANs. Notably, the expression of , whose levels correlate with PD risk, was upregulated by the mild lipid accumulation in N370S/N370S DANs but disrupted in KO DANs. These findings refine the loss-of-function mechanism by associating PD risk levels of GPNMB with lipid levels specific to risk variants.
中的变体是几种突触核蛋白病常见的遗传风险因素。风险增加归因于错误折叠的葡萄糖脑苷脂酶（GCase）的毒性作用（功能获得），以及由于酶活性降低导致的脂质底物积累（功能丧失）。为了阐明其致病性，从一名同时患有1型戈谢病（：N370S/N370S；p.N409S/p.N409S）和帕金森病（PD）的患者中生成了一个诱导多能干细胞系。从该细胞系中，我们创建了一个回复野生型（WT）细胞系和一个基因敲除（KO）细胞系，以消除错误折叠的GCase并加剧脂质积累。与WT多巴胺能神经元（DANs）相比，N370S/N370S和KO多巴胺能神经元（DANs）的GCase水平降低，脂质底物逐渐积累。值得注意的是，其水平与PD风险相关的基因的表达在N370S/N370S DANs中因轻度脂质积累而上调，但在KO DANs中受到破坏。这些发现通过将GPNMB的PD风险水平与特定风险变体的脂质水平相关联，完善了功能丧失机制。
