Amyotrophic lateral sclerosis (ALS) is a fatal non-cell-autonomous neurodegenerative disease characterized by the loss of motor neurons (MNs). Mutations in CRMP4 are associated with ALS in patients, and elevated levels of CRMP4 are suggested to affect MN health in the SOD1G93A -ALS mouse model. However, the mechanism by which CRMP4 mediates toxicity in ALS MNs is poorly understood. Here, by using tissue from human patients with sporadic ALS, MNs derived from C9orf72-mutant patients, and the SOD1G93A -ALS mouse model, we demonstrate that subcellular changes in CRMP4 levels promote MN loss in ALS. First, we show that while expression of CRMP4 protein is increased in cell bodies of ALS-affected MN, CRMP4 levels are decreased in the distal axons. Cellular mislocalization of CRMP4 is caused by increased interaction with the retrograde motor protein, dynein, which mediates CRMP4 transport from distal axons to the soma and thereby promotes MN loss. Blocking the CRMP4-dynein interaction reduces MN loss in human-derived MNs (C9orf72) and in ALS model mice. Thus, we demonstrate a novel CRMP4-dependent retrograde death signal that underlies MN loss in ALS.

• Klíčová slova
• ALS, CRMP4, axonal transport, dynein, retrograde signaling,
• MeSH
• amyotrofická laterální skleróza genetika   metabolismus   MeSH
• axonální transport * MeSH
• axony metabolismus   MeSH
• buněčná smrt MeSH
• buněčné linie MeSH
• dyneiny metabolismus   MeSH
• kultivované buňky MeSH
• motorické neurony metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• signální transdukce MeSH
• superoxid dismutáza 1 genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Dpysl3 protein, mouse MeSH Prohlížeč
• dyneiny MeSH
• proteiny nervové tkáně MeSH
• Sod1 protein, mouse MeSH Prohlížeč
• superoxid dismutáza 1 MeSH

Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal progressive degenerative disorder of motor neurons that overlaps with frontotemporal lobar degeneration (FTLD) clinically, morphologically, and genetically. Although many distinct mutations in various genes are known to cause amyotrophic lateral sclerosis, it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Many of the gene mutations are in proteins that share similar functions. They can be grouped into those associated with cell axon dynamics and those associated with cellular phagocytic machinery, namely protein aggregation and metabolism, apoptosis, and intracellular nucleic acid transport. Analysis of pathways implicated by mutant ALS genes has provided new insights into the pathogenesis of both familial forms of ALS (fALS) and sporadic forms (sALS), although, regrettably, this has not yet yielded definitive treatments. Many genes play an important role, with TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly, C9orf72 being critical genetic players in these neurological disorders. In this mini-review, we will focus on the molecular mechanisms of these two diseases.

• Klíčová slova
• amyotrophic lateral sclerosis, frontotemporal dementia, genetics, neuropathology,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH