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 click here component of the abnormal intracellular inclusions that occur in two common neurodegenerative diseases of humans: (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 luau thank you cards 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 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.