Rab32 connects ER stress to mitochondrial defects in multiple sclerosis

Abstract

BackgroundEndoplasmic 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.MethodsWe 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.ResultsWe 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.ConclusionsER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0788-z) contains supplementary material, which is available to authorized users.

Sural nerve pathology in TFG‐associated motor neuron disease with sensory neuropathy

“…The enlargement of ER lumen is one of ultrastructural hallmarks of ER stress which appeared in axons of myelinated and unmyelinated fibers in our patients. ER stress could lead to mitochondria dysfunction . We observed that the mitochondria became smaller in axons and Schwann cells, which was noted in neurites of cultured neurons with variants of TFG .…”

“…ER stress could lead to mitochondria dysfunction. 27 We observed that the mitochondria became smaller in axons and Schwann cells, which was noted in neurites of cultured neurons with variants of TFG. 14 The abnormal ER and mitochondria might lead to axoplasmic transport dysfunction.…”

Unfolded Protein Response-Dependent Communication and Contact among Endoplasmic Reticulum, Mitochondria and Plasma Membrane.

“…The treatment of human neuroblastoma SH-SY5Y cells with ER stress inducers results in the transcriptional activation of Rab32, indicating that the expression of Rab32 may be under the control of ER stress-induced UPR. The induction of Rab32 in vivo parallels those of ER stress-related genes in active lesions of MS brain77 . Rab32 is also known as a modulator for MAM properties74 .…”

“…upregulated upon brain inflammation in a mouse model and lesions of multiple sclerosis (MS) brain tissues[76][77] . The treatment of human neuroblastoma SH-SY5Y cells with ER stress inducers results in the transcriptional activation of Rab32, indicating that the expression of Rab32 may be under the control of ER stress-induced UPR.…”

The role of oligodendrocytes and their progenitors on neural interface technology: A novel perspective on tissue regeneration and repair

“…Previously, anti-oxidants have been used to reduce the build-up of ROS through either localized drug delivery, systemic administration, or surface modification [152, 259, 260]. Oligodendrocytes and oligodendrocyte precursors are particularly susceptible to these stressors in an ERmediated manner, which is a common method of oligodendroglial loss in neurodegenerative diseases such as MS, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Parkinson’s disease [261, 262]. Using guanabenz for pharmacological inhibition of IFN-γ which phosphorylates PERK, a common ER-stress associated protein, has demonstrated increased oligodendrocyte viability both in vitro and in vivo, reducing clinical symptoms in chronic MS models [263].…”