P3‐007: Loss of Functional Connectivity Is Greater Outside the Default Mode Network in Non‐familial Early‐onset Ad Variants
Year: 2014
Type: article
Abstract: filaments may be observed.The TDP-43 present within these lesions is phosphorylated, truncated and ubiquitinated, and these modifications appear to be abnormal as they are linked to both a cellular heat shock response and microglial activation.The mechanisms associated with this abnormal TDP-43 accumulation are believed to result in a loss of TDP-43 function, perhaps due to the post-translational modifications or resulting from physical sequestration of the TDP-43.The formation of TDP-43 inclusions involves cellular translocation and conversion of TDP-43 into fibrillogenic forms, but the ability of these accumulations to sequester normal TDP-43 and propagate this behavior between neurons pathologically is mostly inferred.The lack of methodology to produce soluble full length TDP-43 and recapitulate this polymerization into filaments as observed in disease has limited our understanding of these pathogenic cascades.Methods: The protocols described here generate soluble, full-length and untagged recombinant TDP-43 allowing for a direct assessment of the impact of various posttranslational modifications on TDP-43 function.Kinases implicated in AD were assessed for their ability to modify TDP-43 aggregation, and the effects of various heat shock proteins on this process were also determined.Results: The results demonstrate that Casein Kinase II (CKII) promotes the polymerization of this soluble recombinant TDP-43 into 10 nm diameter filaments that resemble the most common TDP-43 structures observed in disease.Furthermore, these filaments are recognized as abnormal by Heat Shock Proteins (HSPs) which can inhibit TDP-43 polymerization or directly promote TDP-43 filament depolymerization.Conclusions: These findings demonstrate CKII induces polymerization of soluble TDP-43 into filaments and Hsp70 and 90 promotes TDP-43 filament depolymerization.These findings provides rational for potential therapeutic intervention at these points in TDP-43 proteinopathies.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2139368757