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Regulation of TDP‐43 aggregation by phosphorylation andp62/SQSTM1
Author(s) -
Brady Owen A.,
Meng Peter,
Zheng Yanqiu,
Mao Yuxin,
Hu Fenghua
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.07098.x
Subject(s) - frontotemporal lobar degeneration , ubiquitin , phosphorylation , autophagy , proteasome , signal transducing adaptor protein , protein aggregation , amyotrophic lateral sclerosis , microbiology and biotechnology , inclusion bodies , cytoplasmic inclusion , sequestosome 1 , serine , neurodegeneration , chemistry , biology , cytoplasm , biochemistry , frontotemporal dementia , apoptosis , medicine , pathology , gene , dementia , disease , escherichia coli
J. Neurochem. (2011) 116 , 248–259. Abstract TAR DNA‐binding protein‐43 (TDP‐43) proteinopathy has been linked to several neurodegenerative diseases, such as frontotemporal lobar degeneration with ubiquitin‐positive inclusions and amyotrophic lateral sclerosis. Phosphorylated and ubiquitinated TDP‐43 C‐terminal fragments have been found in cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin‐positive inclusions and amyotrophic lateral sclerosis patients. However, the factors and pathways that regulate TDP‐43 aggregation are still not clear. We found that the C‐terminal 15 kDa fragment of TDP‐43 is sufficient to induce aggregation but the aggregation phenotype is modified by additional sequences. Aggregation is accompanied by phosphorylation at serine residues 409/410. Mutation of 409/410 to phosphomimetic aspartic acid residues significantly reduces aggregation. Inhibition of either proteasome or autophagy dramatically increases TDP‐43 aggregation. Furthermore, TDP‐43 aggregates colocalize with markers of autophagy and the adaptor protein p62/SQSTM1. Over‐expression of p62/SQSTM1 reduces TDP‐43 aggregation in an autophagy and proteasome‐dependent manner. These studies suggest that aggregation of TDP‐43 C‐terminal fragments is regulated by phosphorylation events and both the autophagy and proteasome‐mediated degradation pathways.