UC San Diego

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease symptomatically characterized by progressive, fatal paralysis resulting from the degeneration of the upper and lower motor neurons of the nervous system. Although 10% of ALS is inherited in a dominant, autosomal fashion, the remaining 90% of ALS cases do not have a known genetic cause. Since the discovery of the first gene linked to familial ALS (FALS), much progress has been made towards understanding the pathological mechanisms underlying this disease. Like many neurodegenerative diseases, ALS as well as a second neurodegenerative disease, frontotemporal lobar degeneration (FTLD), are characterized by the appearance of ubiquitinated inclusions within the cytoplasm of neurons and glia. As the most common cause of frontotemporal dementia, a class of neurodegenerative diseases in adults under 65, FTLD shares clinical and pathological signs with ALS. The discovery that the protein TAR DNA binding protein (TDP-43) comprises the major protein component in these ubiquitinated inclusions in ALS and FTLD in 2006 represented a major shift in the understanding of ALS and FTLD pathogenesis. Since 2008, over 40 mutations linked to sporadic and familial ALS have been reported in TDP-43, as well as in a second structurally and functionally related nucleic acid binding protein, FUS/TLS. At present, the mechanism underlying TDP -43 and FUS/TLS-mediated neurodegeneration is not well understood. Much of the molecular understanding of ALS and neurodegeneration pathogenesis comes from the use of genetic models expressing disease-linked mutations in the causative genes. The study presented here demonstrates that mutations in TDP-43 are sufficient to induce adult onset, mutant-dependent neurodegeneration in the absence of robust cytoplasmic accumulation, through the generation and use of rodent models expressing mutant human TDP-43. Furthermore, targets directly bound by TDP-43 are aberrantly spliced in a mutant-dependent, dose-dependent manner, with mutations in TDP-43 conferring both gain and loss of function. Thus, mutant-dependent alterations in splicing may contribute to motor neuron degeneration prior to the accumulation of aberrant cytoplasmic species of TDP -43