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Open Access 01-12-2017 | Research

Rab32 connects ER stress to mitochondrial defects in multiple sclerosis

Authors: Yohannes Haile, Xiaodan Deng, Carolina Ortiz-Sandoval, Nasser Tahbaz, Aleksandra Janowicz, Jian-Qiang Lu, Bradley J. Kerr, Nicholas J. Gutowski, Janet E. Holley, Paul Eggleton, Fabrizio Giuliani, Thomas Simmen

Published in: Journal of Neuroinflammation | Issue 1/2017

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

ER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.

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Title: Rab32 connects ER stress to mitochondrial defects in multiple sclerosis
Authors: Yohannes Haile
Xiaodan Deng
Carolina Ortiz-Sandoval
Nasser Tahbaz
Aleksandra Janowicz
Jian-Qiang Lu
Bradley J. Kerr
Nicholas J. Gutowski
Janet E. Holley
Paul Eggleton
Fabrizio Giuliani
Thomas Simmen
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0788-z

At a glance: The STEP trials

Springer Medicine

Rab32 connects ER stress to mitochondrial defects in multiple sclerosis

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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