Altered SYNJ2BP-mediated mitochondrial-ER contacts in motor neuron disease

Naemeh Pourshafie; Ester Masati; Amber Lopez; Eric Bunker; Allison Snyder; Nancy A Edwards; Audrey M Winkelsas; Kenneth H Fischbeck; Christopher Grunseich

doi:10.1016/j.nbd.2022.105832

Altered SYNJ2BP-mediated mitochondrial-ER contacts in motor neuron disease

Neurobiol Dis. 2022 Oct 1:172:105832. doi: 10.1016/j.nbd.2022.105832. Epub 2022 Jul 27.

Authors

Naemeh Pourshafie¹, Ester Masati², Amber Lopez³, Eric Bunker⁴, Allison Snyder⁵, Nancy A Edwards⁶, Audrey M Winkelsas⁷, Kenneth H Fischbeck⁸, Christopher Grunseich⁹

Affiliations

¹ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: naemeh.pourshafie@nih.gov.
² Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: em3cb@virginia.edu.
³ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: eric.bunker@nih.gov.
⁵ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: allison.snyder@nih.gov.
⁶ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: edwardsn@ninds.nih.gov.
⁷ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: audrey.winkelsas@nih.gov.
⁸ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: fischbeck@ninds.nih.gov.
⁹ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Electronic address: christopher.grunseich@nih.gov.

PMID: 35907632
DOI: 10.1016/j.nbd.2022.105832

Abstract

Synaptojanin 2 binding protein (SYNJ2BP) is an outer mitochondrial membrane protein with a cytosolic PDZ domain that functions as a cellular signaling hub. Few studies have evaluated its role in disease. Here we use induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem tissue from patients with two hereditary motor neuron diseases, spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis type 4 (ALS4), and show that SYNJ2BP expression is increased in diseased motor neurons. Similarly, we show that SYNJ2BP expression increases in iPSC-derived motor neurons undergoing stress. Using proteomic analysis, we found that elevated SYNJ2BP alters the cellular distribution of mitochondria and increases mitochondrial-ER membrane contact sites. Furthermore, decreasing SYNJ2BP levels improves mitochondrial oxidative function in the diseased motor neurons. Together, our observations offer new insight into the molecular pathology of motor neuron disease and the role of SYNJ2BP in mitochondrial dysfunction.

Keywords: Motor neuron disease; Polyglutamine disease; Spinal and bulbar muscular atrophy.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Humans
Membrane Proteins / metabolism
Mitochondria / metabolism
Motor Neuron Disease* / metabolism
Motor Neurons / pathology
Muscular Atrophy, Spinal* / pathology
Proteomics

Substances

Membrane Proteins
SYNJ2BP protein, human