VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans.

Sung Min Han,Jeevan K Prasain,Jelena Scekic-Zahirovic,Michael A Miller,Pauline Cottee,Luc Dupuis,Jack Vibbert,Hugo J Bellen,Hajer El Oussini,Kaveh Ashrafi

doi:10.1371/journal.pgen.1003738

Abstract

Mutations in VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), two motor neuron diseases that often include alterations in energy metabolism. We have shown that C. elegans and Drosophila neurons secrete a cleavage product of VAPB, the N-terminal major sperm protein domain (vMSP). Secreted vMSPs signal through Roundabout and Lar-like receptors expressed on striated muscle. The muscle signaling pathway localizes mitochondria to myofilaments, alters their fission/fusion balance, and promotes energy production. Here, we show that neuronal loss of the C. elegans VAPB homolog triggers metabolic alterations that appear to compensate for muscle mitochondrial dysfunction. When vMSP levels drop, cytoskeletal or mitochondrial abnormalities in muscle induce elevated DAF-16, the Forkhead Box O (FoxO) homolog, transcription factor activity. DAF-16 promotes muscle triacylglycerol accumulation, increases ATP levels in adults, and extends lifespan, despite reduced muscle mitochondria electron transport chain activity. Finally, Vapb knock-out mice exhibit abnormal muscular triacylglycerol levels and FoxO target gene transcriptional responses to fasting and refeeding. Our data indicate that impaired vMSP signaling to striated muscle alters FoxO activity, which affects energy metabolism. Abnormalities in energy metabolism of ALS patients may thus constitute a compensatory mechanism counterbalancing skeletal muscle mitochondrial dysfunction.

Highlights

amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by the combined degeneration of lower and upper motor neurons [1]
ALS patients often present with systemic alterations in energy metabolism, such as dyslipidemia and hypermetabolism of unknown origin
We have shown that neurons secrete the N-terminal VAPB vMSP into the extracellular environment

Summary

Introduction

ALS is a lethal neurodegenerative disease characterized by the combined degeneration of lower and upper motor neurons [1]. Most ALS cases occur sporadically, but about 10% are familial. These genetic cases are caused by mutations in multiple genes, including in the Vapb (VAMP/synaptobrevin-associated protein B) gene. Mutations in Vapb lead to ALS8 that manifests as ALS or late-onset SMA, a motor neuron disease restricted to lower motor neurons [2,3,4]. While Vapb mutations are rare, reduced VAPB mRNA or protein levels have been reported in sporadic ALS patients, a mSOD1 ALS mouse model, and ALS8 patient motor neurons derived from induced pluripotent stem cells [5,6,7]. A loss of VAPB might be relevant in nonALS8 patients

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