Deregulation of mTORC1-TFEB axis in human iPSC model of GBA1-associated Parkinson’s disease

Frontiers in Neuroscience

Neuroscience

Chinmoy Sarkar¹  Marta M. Lipinski²  Afsoon Saadin³  Fahad Mubariz³  Nicholas Lingenfelter³  Ola Awad³  Aditi Banerjee⁴ 

[1] Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, United States;Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, United States;Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States;Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States;Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States;

关键词: GBA1;    Parkinson’s disease;    transcription factor EB;    induced-pluripotent stem cells;    autophagy-lysosomal pathway;    mammalian target of rapamycin complex1;   

DOI  :  10.3389/fnins.2023.1152503

 received in 2023-01-27, accepted in 2023-05-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

Mutations in the GBA1 gene are the single most frequent genetic risk factor for Parkinson’s disease (PD). Neurodegenerative changes in GBA1-associated PD have been linked to the defective lysosomal clearance of autophagic substrates and aggregate-prone proteins. To elucidate novel mechanisms contributing to proteinopathy in PD, we investigated the effect of GBA1 mutations on the transcription factor EB (TFEB), the master regulator of the autophagy-lysosomal pathway (ALP). Using PD patients’ induced-pluripotent stem cells (iPSCs), we examined TFEB activity and regulation of the ALP in dopaminergic neuronal cultures generated from iPSC lines harboring heterozygous GBA1 mutations and the CRISPR/Cas9-corrected isogenic controls. Our data showed a significant decrease in TFEB transcriptional activity and attenuated expression of many genes in the CLEAR network in GBA1 mutant neurons, but not in the isogenic gene-corrected cells. In PD neurons, we also detected increased activity of the mammalian target of rapamycin complex1 (mTORC1), the main upstream negative regulator of TFEB. Increased mTORC1 activity resulted in excess TFEB phosphorylation and decreased nuclear translocation. Pharmacological mTOR inhibition restored TFEB activity, decreased ER stress and reduced α-synuclein accumulation, indicating improvement of neuronal protiostasis. Moreover, treatment with the lipid substrate reducing compound Genz-123346, decreased mTORC1 activity and increased TFEB expression in the mutant neurons, suggesting that mTORC1-TFEB alterations are linked to the lipid substrate accumulation. Our study unveils a new mechanism contributing to PD susceptibility by GBA1 mutations in which deregulation of the mTORC1-TFEB axis mediates ALP dysfunction and subsequent proteinopathy. It also indicates that pharmacological restoration of TFEB activity could be a promising therapeutic approach in GBA1-associated neurodegeneration.

【 授权许可】

Unknown   
Copyright © 2023 Mubariz, Saadin, Lingenfelter, Sarkar, Banerjee, Lipinski and Awad.