Proteomics

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Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains


ABSTRACT: TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD-TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of neurodegeneration. However, most of the post-translational modifications or truncation sites in the abnormal TDP-43 in brains of patients remain to be identified by protein chemical analysis. In this study, we carried out a highly sensitive liquid chromatography-mass spectrometry analysis of Sarkosyl-insoluble pathological TDP-43 from brains of ALS patients and identified several novel phosphorylation sites, deamidation sites, and cleavage sites. Almost all modifications were localized in the Gly-rich C-terminal half. Most of the cleavage sites identified in this study are novel and are located in N-terminal half, suggesting that these sites may be more accessible to proteolytic enzymes. The data obtained in this study provide a foundation for the molecular mechanisms of TDP-43 aggregation and ALS pathogenesis.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Fuyuki Kametani 

PROVIDER: PXD012920 | JPOST Repository | Sun Mar 01 00:00:00 GMT 2020

REPOSITORIES: jPOST

Dataset's files

Source:
Action DRS
case1fraction2chmo.raw Raw
case1fraction2tryp.raw Raw
case1fraction3chymo.raw Raw
case1fraction3tryp.raw Raw
case1fraction4chymo.raw Raw
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Publications

Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains.

Kametani Fuyuki F   Obi Tomokazu T   Shishido Takeo T   Akatsu Hiroyasu H   Murayama Shigeo S   Saito Yuko Y   Yoshida Mari M   Hasegawa Masato M  

Scientific reports 20160316


TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD-TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of n  ...[more]

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