title: A 43-kDa TDP-43 species is present in aggregates associated with frontotemporal lobar degeneration.
abstract: 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: (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 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.
authors.affiliation: Division of Neurology, Denver Health Medical Center, Denver, Colorado, United States of America. patrick.bosque@dhha.org
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bosque
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Boyer
authors.forename: Priya
authors.initials: P
authors.lastname: Mishra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D003902:Detergents; D004587:Electrophoresis, Agar Gel; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D010766:Phosphorylation; D011489:Protein Denaturation; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D014020:Tissue Extracts
chemical_list: D004268:DNA-Binding Proteins; D003902:Detergents; D014020:Tissue Extracts