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Mubariz, Fahad; Saadin, Afsoon; Lingenfelter, Nicholas; Sarkar, Chinmoy; Banerjee, Aditi; Lipinski, Marta M; Awad, Ola
Frontiers in neuroscience, 06/2023, Letnik: 17Journal Article
Mutations in the gene are the single most frequent genetic risk factor for Parkinson's disease (PD). Neurodegenerative changes in -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 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 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 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 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 -associated neurodegeneration.
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