The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases.Abnormal protein aggregation is a hallmark of most inherited and acquired neurodegenerative diseases. Recently, TDP-43 was identified as a component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) 4 (1). The subsequent finding of mutations in TDP-43 in cases of inherited ALS indicates that TDP-43 can be directly involved in the pathogenesis of at least the familial forms of this disease (2-6). It is notable that although aggregates of a particular protein are initially associated with a specific clinical and pathologic syndrome, they are often observed in multiple other neurodegenerative disorders. For example, although cytoplasmic inclusions of TDP-43 were initially described in ALS and FTLD, they have also been observed in Alzheimer disease, diffuse Lewy body disease, dementia pugilistica, Huntington disease, and even inclusion body myopathies (7-11). Whether TDP-43 translocation to the cytosol and aggregation plays a direct role in the pathogenesis of these disorders, or instead is part of a more general cellular stress response, remains to be elucidated (12).Polyglutamine diseases are a family of neurodegenerative disorders caused by expansion of a CAG trinucleotide repeat in the coding regions of certain genes. Examples include Huntington disease, X-linked spinal-bulbar muscular atrophy, and several of the spinocerebellar ataxias (13-15). Expanded polyglutamine proteins have a ...

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