Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin

• DOI: 10.1523/jneurosci.0109-15.2015
• Publication Date: 2015-09-16T16:33:41Z
• Authors: Almas Siddiqui; Dipa Bhaumik; Shankar J. Chinta; Anand Rane; Subramanian Rajag...; Christopher A. Lieu; Gordon J. Lithgow; Julie K. Andersen
• Keywords: TFEB; PINK1

Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result both familial and sporadic forms Parkinson's disease (PD) conjunction with reductions removal damaged mitochondria. In contrast what has been reported for other PARK2 mutations, expression Q311X mutation vivo mice appears involve a downstream step autophagic pathway at level lysosomal function. This coincides increased PARIS reduced reciprocal signaling involving master regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) transcription factor EB (TFEB). Treatment rapamycin was found independently restore PGC1α-TFEB manner not requiring activity abrogate impairment quality control neurodegenerative features associated this model. Losses cultured rat DAergic cells expressing function cell viability were be PARIS-dependent restored TFEB. Studies human iPSC-derived neurons demonstrate that TFEB induction can mitochondrially compromised Based on data, we propose impacts via PARIS-mediated regulation upregulation SIGNIFICANCE STATEMENT are generally loss ability interact impacting initiation. Our data suggest that, case least one mutation, Q311X, detrimental effects due inhibition Mechanistically, involves elevations protein levels subsequent normally regulates control. restores abrogates neuronal loss. Taken total, our rapamycin.