title: Rab32 connects ER stress to mitochondrial defects in multiple sclerosis.
abstract: Endoplasmic reticulum (ER) stress is a hallmark of neurodegenerative diseases such as multiple sclerosis (MS). However, this physiological mechanism has multiple manifestations that range from impaired clearance of unfolded proteins to altered mitochondrial dynamics and apoptosis. While connections between the triggering of the unfolded protein response (UPR) and downstream mitochondrial dysfunction are poorly understood, the membranous contacts between the ER and mitochondria, called the mitochondria-associated membrane (MAM), could provide a functional link between these two mechanisms. Therefore, we investigated whether the guanosine triphosphatase (GTPase) Rab32, a known regulator of the MAM, mitochondrial dynamics, and apoptosis, could be associated with ER stress as well as mitochondrial dysfunction.
  
  
  
  We assessed Rab32 expression in MS patient and experimental autoimmune encephalomyelitis (EAE) tissue, via observation of mitochondria in primary neurons and via monitoring of survival of neuronal cells upon increased Rab32 expression.
  
  
  
  We found that the induction of Rab32 and other MAM proteins correlates with ER stress proteins in MS brain, as well as in EAE, and occurs in multiple central nervous system (CNS) cell types. We identify Rab32, known to increase in response to acute brain inflammation, as a novel unfolded protein response (UPR) target. High Rab32 expression shortens neurite length, alters mitochondria morphology, and accelerates apoptosis/necroptosis of human primary neurons and cell lines.
  
  
  
  ER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada.|Present address: Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Haile
authors.affiliation: Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Canada.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ortiz-Sandoval
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada.
authors.forename: Nasser
authors.initials: N
authors.lastname: Tahbaz
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Janowicz
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
authors.forename: Jian-Qiang
authors.initials: JQ
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Kerr
authors.affiliation: University of Exeter Medical School & Neurology Department, Royal Devon & Exeter Hospital, Exeter, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Gutowski
authors.affiliation: University of Exeter Medical School & Neurology Department, Royal Devon & Exeter Hospital, Exeter, UK.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Holley
authors.affiliation: University of Exeter Medical School & Neurology Department, Royal Devon & Exeter Hospital, Exeter, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Eggleton
authors.affiliation: Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Canada. giuliani@ualberta.ca.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giuliani
authors.affiliation: Department of Cell Biology, University of Alberta, Edmonton, Canada. Thomas.Simmen@ualberta.ca.
authors.forename: Thomas
authors.identifier: 0000-0002-2350-2965
authors.initials: T
authors.lastname: Simmen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000166:cytology; D037281:Calnexin / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005333:Fetus; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000473:pathology; D009103:Multiple Sclerosis / Q000150:complications* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure*; D051742:Transcription Factor CHOP / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D016207:Cytokines; C497249:DDIT3 protein, human; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C499638:PACS2 protein, human; D033921:Vesicular Transport Proteins; C053387:endoplasmin; D037281:Calnexin; D051742:Transcription Factor CHOP; C466094:Rab32 protein, human; D020691:rab GTP-Binding Proteins
keywords: Endoplasmic reticulum; Mitochondria; Multiple sclerosis; Unfolded protein response (UPR)