Peripherin-mediated death of motor neurons rescued by overexpression of neurofilament NF-H proteins.
In previous studies, we showed that overexpression of peripherin, a neuronal intermediate filament (IF) protein, in mice deficient for neurofilament light (NF-L) subunits induced a progressive adult-onset degeneration of spinal motor neurons characterized by the presence of IF inclusion bodies reminiscent of axonal spheroids found in amyotrophic lateral sclerosis (ALS). In contrast, the overexpression of human neurofilament heavy (NF-H) proteins provoked the formation of massive perikaryal IF protein accumulations with no loss of motor neurons. To further investigate the toxic properties of IF protein inclusions, we generated NF-L null mice that co-express both peripherin and NF-H transgenes. The axonal count in L5 ventral roots from 6 and 8-month-old transgenic mice showed that NF-H overexpression rescued the peripherin-mediated degeneration of motor neurons. Our analysis suggests that the protective effect of extra NF-H proteins is related to the sequestration of peripherin into the perikaryon of motor neurons, thereby abolishing the development of axonal IF inclusions that might block transport. These findings illustrate the importance of IF protein stoichiometry in formation, localization and toxicity of neuronal inclusion bodies.
Beaulieu
Jean-Martin
JM
Centre for Research in Neurosciences, McGill University, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
Julien
Jean-Pierre
JP
D000690:Amyotrophic Lateral Sclerosis / Q000517:prevention & control*; D000818:Animals; D016923:Cell Death / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D008161:Lumbosacral Region; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D016900:Neurofilament Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D064531:Peripherins; D021381:Protein Transport / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D019076:Transgenes
D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C578994:PRPH protein, human; D064531:Peripherins; C044882:neurofilament protein L; C051774:neurofilament protein H; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases