Rodent Models of Amyotrophic Lateral Sclerosis.
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (∼ 40% to 50% of fALS and ∼ 10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disorder is mediated non-cell autonomously, i.e., not only motor neurons are involved, but glial cells including microglia, astrocytes, and oligodendrocytes, and other neuronal subpopulations are also implicated in the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models.
Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
Thomas
T
Philips
Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
Jeffrey D
JD
Rothstein
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D051381:Rats; D011922:Rats, Mutant Strains; D055647:Rats, Transgenic; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
Amyotrophic Lateral Sclerosis; RNA processing alterations; aberrant protein homeostasis; glia; motor neuron; rodent models