title: Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-alpha.
abstract: Peripherin, a neuronal intermediate filament protein associated with axonal spheroids in amyotrophic lateral sclerosis (ALS), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. To further clarify the selectivity and mechanism of peripherin-induced neuronal death, we analyzed the effects of peripherin overexpression in primary neuronal cultures. Peripherin overexpression led to the formation of cytoplasmic protein aggregates and caused the death not only of motor neurons, but also of dorsal root ganglion (DRG) neurons that were cultured from dissociated spinal cords of peripherin transgenic embryos. Apoptosis of DRG neurons containing peripherin aggregates was dependent on the proinflammatory central nervous system environment of spinal cultures, rich in activated microglia, and required TNF-alpha. This synergistic proapoptotic effect may contribute to neuronal selectivity in ALS.
authors.affiliation: Centre for Research in Neurosciences, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Robertson
authors.forename: J M
authors.initials: JM
authors.lastname: Beaulieu
authors.forename: M M
authors.initials: MM
authors.lastname: Doroudchi
authors.forename: H D
authors.initials: HD
authors.lastname: Durham
authors.forename: J P
authors.initials: JP
authors.lastname: Julien
authors.forename: W E
authors.initials: WE
authors.lastname: Mushynski
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000648:ultrastructure; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000648:ultrastructure*; D008562:Membrane Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D008845:Microinjections; D009046:Motor Neurons / Q000648:ultrastructure*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000648:ultrastructure*; D064531:Peripherins; D013116:Spinal Cord / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D064531:Peripherins; D014409:Tumor Necrosis Factor-alpha