The critical role of membralin in postnatal motor neuron survival and disease
Bo Yang,
Mingliang Qu,
Rengang Wang,
Jon E Chatterton,
Xiao-Bo Liu,
Bing Zhu,
Sonoko Narisawa,
Jose Luis Millan,
Nobuki Nakanishi,
Kathryn Swoboda,
Stuart A Lipton,
Dongxian Zhang
Affiliations
Bo Yang
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Mingliang Qu
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Rengang Wang
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Jon E Chatterton
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Xiao-Bo Liu
Electron Microscopy Laboratory, Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, United States
Bing Zhu
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Sonoko Narisawa
Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Jose Luis Millan
Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Nobuki Nakanishi
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Kathryn Swoboda
Department of Neurology, Massachusetts General Hospital, Boston, United States
Stuart A Lipton
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States; Department of Neuroscience, School of Medicine, University of California, San Diego, La Jolla, United States
Dongxian Zhang
Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5–6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.
