A 43-kDa TDP-43 species is present in aggregates associated with frontotemporal lobar degeneration.

A 43-kDa TDP-43 species is present in aggregates associated with frontotemporal lobar degeneration.

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The transactive response DNA-binding protein (TDP-43) is a major component of the abnormal intracellular inclusions that occur in two common neurodegenerative diseases of humans: Drone (1) a subtype of frontotemporal lobar degeneration and (2) amyotrophic lateral sclerosis.Genetics, experiments in cultured cells and animals, and analogy with other neurodegenerative diseases indicate that the process of TDP-43 aggregation is fundamental to the pathogenesis of these 2 diseases, but the process by which this aggregation occurs is not understood.Biochemical fractionation has revealed truncated, phosphorylated and ubiquitinated forms of TDP-43 in a detergent-insoluble fraction from diseased CNS tissue, while these forms are absent from controls.However, a large amount of the normally predominant 43-kDa form of TDP-43 is present in the detergent-insoluble fraction even from control brains, so it has not been possible to determine if this form of TDP-43 is part of pathological aggregates in frontotemporal lobe degeneration.We used semi-denaturing detergent-agarose gel electrophoresis to isolate high molecular weight aggregates containing TDP-43 that are present in the cerebral cortex of individuals with frontotemporal lobar degeneration but not that of controls.

These aggregates include the same covalently modified forms of TDP-43 seen in detergent-insoluble extracts.In addition, aggregates include a 43-kDa Bicycle Accessories TDP-43 species.This aggregated 43-kDa form of TDP-43 is absent or present only at low levels in controls.The presence of 43-kDa TDP-43 in aggregates raises the possibility that covalent modification is not a primary step in the pathogenic aggregation of TDP-43 associated with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.