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

作者：Kametani Fuyuki; Obi Tomokazu; Shishido Takeo; Akatsu Hiroyasu; Murayama Shigeo; Saito Yuko; Yoshida Mari; Hasegawa Masato

来源：Scientific Reports, 2016, 6(1): 23281.

DOI：10.1038/srep23281

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

• 出版日期2016-3-16