Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease inherited in a small subset of patients. The SOD1(G93A) transgenic mouse models this subset of patients, and studies of this strain have suggested that endoplasmic reticulum (ER) stress and deficits in ER chaperone function are contributors to ALS pathophysiology. Here, we demonstrate that the reticulon family of proteins is a novel regulator of the ER chaperone protein disulfide isomerase (PDI), and that through PDI, reticulon-4A (Nogo-A) can protect mice against the neurodegeneration that characterizes ALS. We show that overexpressing reticulon protein induces a punctate redistribution of PDI intracellularly, both in vitro and in vivo. Conversely, reduction of endogenous NogoA expression causes a more homogeneous expression pattern in vivo. These effects occur without induction of the unfolded protein response. To examine the effect of PDI redistribution on ALS disease progression, we conducted survival and behavior studies of SOD1(G93A) mice. Deletion of a single copy of the NogoA,B gene accelerates disease onset and progression, while deletion of both copies further worsens disease. We conclude that NogoA contributes to the proper function of the ER resident chaperone PDI, and is protective against ALS-like neurodegeneration. Our results provide a novel intracellular role for reticulon proteins and support the hypothesis that modulation of PDI function is a potential therapeutic approach to ALS.
Yang
Yvonne S
YS
Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Harel
Noam Y
NY
Strittmatter
Stephen M
SM
D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005998:Glycine / Q000235:genetics; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000502:physiology; D009185:Myelin Proteins / Q000096:biosynthesis* / Q000235:genetics; D018696:Neuroprotective Agents / Q000378:metabolism; D000070798:Nogo Proteins; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D014018:Tissue Distribution / Q000502:physiology
D018832:Molecular Chaperones; D009185:Myelin Proteins; D018696:Neuroprotective Agents; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019704:Protein Disulfide-Isomerases; D000409:Alanine; D005998:Glycine