biostudies-literatureUnknown6Jiang LLTDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311-360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region formsScientific reports23928https://www.ebi.ac.uk/biostudies/studies/S-EPMC4814915biostudies-literatureTwo mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation.PMC4814915Yang HHe WTChe MXHu HYYin XFJiang LLZhao JfalseTwo mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation.TDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311-360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region forms2016-01-01T00:00:00Z2016 Mar2026-04-14T21:21:23.649Z2019-03-27T03:10:44ZS-EPMC48149152703029210.1038/srep23928