Objective: To investigate markers of macroautophagy and mitochondrial dynamics in fibroblasts and postmortem brain of Parkinson’s disease (PD) patients with glucoerebrosidase (GBA1) mutations and controls.

Background: Mutations in the GBA1 gene are the common genetic risk factors for PD, and how GBA1 mutations could lead to cellular pathology remain poorly understood.

Methods: We studied macroautophagy markers (LC3-II, p62, mTOR) and makers for mitochondrial dynamics (porin, Drp1, Fis1, Mfn1, Opa1) in the postmortem cingular cortex of PD patients with GBA1 mutations (n = 5), sporadic PD patients without GBA1 or LRRK2 mutations (n = 6), or age -matched controls (n = 4). We additionally studied these markers in the untransformed fibroblasts from 8 PD patients with GBA1 mutations and 7 age-matched controls.

Results: We found that PD brain with GBA1 mutations had increased LC3-II and p62 levels, indicating macroautophagy dysfunction. In addition, the ratio of phopho-mTOR and total mTOR was decreased in PD brain with GBA1 mutation, suggesting an inhibition of mTOR activity. We also found increased mitochondrial mass and altered mitochondrial fission and fusion protein levels. Similarly, fibroblasts from PD patients with GBA1 mutations also demonstrated macroautophagy deregulation, disrupted mitochondrial dynamics and mitochondria dysfunction, including decreased mitochondrial membrane potential and increased mitochondrial reactive oxygen species.

Conclusions: Our data suggested GBA1 mutations could interrupt mTOR and macroautophagy pathways and lead to impaired energy and free radical homeostasis in mitochondria.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dysregulated-macroautophagy-and-mitochondrial-dynamics-in-pd-with-glucocerebrosidase-mutations/