Deciphering Amyotrophic Lateral Sclerosis: What Phenotype, Neuropathology and Genetics Are Telling Us about Pathogenesis
Baloh, Robert H.
Brooks, Benjamin Rix
Floeter, Mary Kay
Van Den Berg, Leonard
Ringel, StevenNote: Order does not necessarily reflect citation order of authors.
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CitationRavits, John, Stanley Appel, Robert H. Baloh, Richard Barohn, Benjamin Rix Brooks, Lauren Elman, Mary Kay Floeter, et al. 2013. Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 14(Suppl 1): 5-18.
AbstractAmyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron
(LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. But they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they all are characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly
heterogeneous, each mutated gene has its own genetic and molecular signature. Putting this together, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS and ALS is a syndrome. But since multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principle component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms can be identified and understood, ALS therapy could rationally target progression and stop disease—a goal that seems increasingly achievable.
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