TDP-43 proteinopathy: tracing the roots of a newly classified neurodegenerative disease
Kornfield, James M.
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TAR DNA Binding Protein-43 (TDP-43) proteinopathy is a disease pathology that underlies a broad field of neurodegenerative disorders. Most prominently, TDP-43 aggregates are the hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The implication of TDP-43 in ALS, in particular, has helped initiate a cascade of research to determine the properties of the previously obscure protein. From these studies, it is now known that TDP-43 is a DNA and RNA binding protein, important for the splicing and regulation of many transcripts. In the disease state, TDP-43 is modified in a way that fuels its accumulation into cytoplasmic aggregates called inclusions. This paper will delineate the current understanding of the mechanisms behind TDP-43 proteinopathy and the resultant clinical conditions. The body of evidence firmly supports a clinical spectrum of TDP-43 proteinopathy that ranges between pure motor neuron disease (MND) and pure frontotemporal dementia (FTD). It also appears that the root cause of neurodegeneration in these disorders comes about through a combination of a gain of toxic function and a loss of normal TDP-43. Continued research into the molecular processes leading to the capitulation of TDP-43 holds great promise for the development of new drug targets to help treat the spectrum of TDP-43 proteinopathy.
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