title: Amyotrophic lateral sclerosis: a novel hypothesis involving a gained 'loss of function' in the JNK/SAPK pathway.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that mainly affects motor neurons. Despite intensive research efforts inspired by the mile-stone discovery linking the Cu/Zn superoxide dismutase 1 (SOD1) gene to a subset of familial cases, the mechanisms underlying disease pathogenesis are still largely unknown. Nonetheless, the recent finding of a second gene associated with familial form of the disease, ALS2, is likely to be of great help in elucidating the key pathways involved in motor neuron degeneration. Here, we provide evidence that the JNK/SAPK pathway plays a critical neuroprotective role in susceptible motor neurons in ALS. The involvement of the JNK/SAPK pathway integrates our knowledge about these two known genetic factors into a single pathogenic pathway involved in both sporadic and familial ALS.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. xxz12@po.cwru.edu
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D005609:Free Radicals; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: C438187:ALS2 protein, human; D005609:Free Radicals; D020662:Guanine Nucleotide Exchange Factors; D013482:Superoxide Dismutase; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases