title: TDP-43-The key to understanding amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration leading to progressive muscle atrophy, weakness, paralysis and death. The majority of ALS (>95%) shows intracellular aggregation of transactive response DNA binding protein (TDP-43) as a prominent pathological feature. TDP-43 is normally a nuclear protein. In ALS, TDP-43 accumulates and aggregates in the cytoplasm (thus forming TDP-43 proteinopathy) and is depleted from the nucleus in CNS cells, including motor neurons and glia. While TDP-43 aggregation can harm cells through a gain of toxicity, it can also cause a loss of TDP-43 function in conjunction with its nuclear depletion. TDP-43 regulates its own expression to maintain itself at a constant level. Perturbation of this level by either increasing or decreasing TDP-43 in animal models leads to neurodegeneration and ALS phenotypes. The evidence supports the hypothesis that TDP-43 dysfunction is a critical driver of neurodegeneration in the vast majority of ALS cases.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology; University of Massachusetts; Worcester, MA USA; RNA Therapeutic Institute; University of Massachusetts; Worcester, MA USA; Department of Cell Biology; University of Massachusetts; Worcester, MA USA; Neuroscience Program; University of Massachusetts Medical School; Worcester, MA USA.
authors.forename: Zuoshang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Pharmacology; University of Massachusetts ; Worcester, MA USA.
authors.forename: Chunxing
authors.initials: C
authors.lastname: Yang
keywords: FTD; FTLD; frontotemporal dementia; gain of function; loss of function; motoneuron; neurological disease