PRKN/parkin-mediated control of SNCA (synuclein alpha) and chaperone-mediated autophagy are defective in cellular, mice models and Parkinson disease-affected brains.

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Pathological accumulation of toxic SNCA species and loss of E3-ligase function of PRKN are two key features observed in Parkinson disease (PD). Here, we established the contribution of an E3-ligase-independent transcriptional function of PRKN in SNCA regulation. PRKN depletion decreased SNCA and GBA1 (glucosylceramidase beta 1) mRNA levels and reduced CMA-driven degradation of SNCA, thereby triggering the accumulation of its phosphorylated aggregation-prone toxic species. We established that PRKN controls the CMA player LAMP2A but not HSPA8/HSC70 in isolated lysosomal fractions prepared from human neuronal and mouse fibroblastic cells. Further, we showed that PRKN-associated regulation of LAMP2 is isoform specific. We showed that PRKN-mediated control of SNCA, GBA1 and LAMP2A occurs in vivo and is impaired in the paraquat-treated PD mice model. We showed that the levels of phosphorylated SNCA and PRKN are correlated in sporadic PD human brain samples and that fibroblasts of patients carrying pathogenic PRKN mutations exhibit impaired CMA activity. Our study decrypts a new molecular mechanism linking three PD major therapeutic targets. It enriches the portfolio of transcriptional targets of PRKN and establishes PRKN as a novel CMA regulator. Further, it shows that PRKN controls both direct and indirect (GBA1-dependent) transcriptional regulation of SNCA. This novel molecular cascade opens potential new avenues in PD treatment.Abbreviations: ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; ΔPkPr: deleted PRKN-RE Snca promoter; GBA1: glucosylceramidase beta 1; HAP1: human haploid cell; GBA1+: human haploid control cells; GBA-: human haploid invalidated for GBA1 cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; MEF: mouse embryonic fibroblast; Prkn+/+: MEF and mice Prkn control; prkn-/-: MEF and mice prkn knockout; PD: Parkinson disease; PQ: paraquat; PRKN: parkin RBR E3 ubiquitin protein ligase; PRKN-RE: PRKN responsive element; PRKN [SC]: PRKN control; PRKN [KD]: PRKN-depleted; SNCA: synuclein alpha; SNCA [M]: monomeric synuclein alpha; SNCA [O]: oligomeric synuclein alpha; SNCA p-S129: phosphorylated synuclein alpha, SPD: sporadic Parkinson disease; TF: transcription factor; TH: tyrosine hydroxylase; WTPr: wild-type Snca promoter.

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