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Acta Neuropathol Commun. 2019 Oct 15;7(1):154. doi: 10.1186/s40478-019-0806-3.

Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy.

Author information

1
Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany.
2
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
3
Department of Pediatrics, University Hospital Cologne, Cologne, Germany.
4
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
5
Department of Health Sciences, College of Public Health and the Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
6
Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7
Institute for Genetics, University of Cologne, Cologne, Germany.
8
Center for Rare Disease Cologne, University Hospital Cologne, Cologne, Germany.
9
Institute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany.
10
Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany. Min.kye@uk-koeln.de.

Abstract

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

KEYWORDS:

CTRP3; Motor neuron disease; Muscle secretome; Neuronal protein synthesis; SMN (survival motor neuron); Spinal muscular atrophy

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