Mitochondrial dysfunction and mitophagy defect triggered by heterozygous <i>GBA</i> mutations
Creators: name: Li, Hongyu
name: Ham, Ahrom
name: Chi, Thong
name: Kuo, Sheng-Han
name: Kanter, Ellen
name: Kim, Donghoon
name: Seok Ko, Han
name: Quan, Yi
name: Pablo Sardi, Sergio
name: Li, Aiqun
name: Arancio, Ottavio
name: Kang, Un Jung
name: Sulzer, David
name: Tang, Guomei
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biophysics
subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Neuroscience
subject: Physiology
subject: Immunology
subject: FOS: Clinical medicine
subject: Cancer

description: Heterozygous mutations in <i>GBA</i>, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in <i>Gba</i><sup>L444P/WT</sup> knockin mice, the L444P heterozygous <i>Gba</i> mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of <i>GBA</i> inhibited lysosomal clearance of autophagic cargo. The link between heterozygous <i>GBA</i> mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous <i>GBA</i> mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with <i>GBA</i> heterozygous mutations. <b>Abbreviations:</b> AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide <i>3</i>-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous <i>GBA</i> mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without <i>GBA</i> mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type