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

Neurobiology of Disease (Oct 2022)

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

Affiliations

Naemeh Pourshafie: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Corresponding authors at: 2A-1010, Building 35, 35 Convent Drive, National Institutes of Health, Bethesda, MD 20892, USA.
Ester Masati: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Amber Lopez: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Eric Bunker: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Allison Snyder: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Nancy A. Edwards: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Audrey M. Winkelsas: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Kenneth H. Fischbeck: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Christopher Grunseich: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Corresponding authors at: 2A-1010, Building 35, 35 Convent Drive, National Institutes of Health, Bethesda, MD 20892, USA.

Journal volume & issue: Vol. 172
p. 105832

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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