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P3‐005: A CASE SERIES OF GRN MUTATIONS FROM GERMAN‐SPEAKING COUNTRIES
Author(s) -
MuellerSarnowski Felix,
Capell Anja,
Rujescu Dan,
Buerger Katharina,
DiehlSchmid Janine,
Perneczky Robert,
Arnim Christine A.F.,
Schneider Susanne,
Jung Hans,
Neumann Manuela,
Biskup Saskia,
Danek Adrian
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.05.1092
Subject(s) - context (archaeology) , c9orf72 , frontotemporal lobar degeneration , mutation , tardbp , disease , medicine , genetics , frontotemporal dementia , gene , biology , dementia , paleontology
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.