Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway

被引:21
作者
Araki, Wataru [1 ]
Minegishi, Seiji [1 ]
Motoki, Kazumi [1 ]
Kume, Hideaki [1 ]
Hohjoh, Hirohiko [2 ]
Araki, Yumiko M. [1 ,3 ]
Tamaoka, Akira [4 ]
机构
[1] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Demyelinating Dis & Aging, Kodaira, Tokyo 1878502, Japan
[2] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mol Pharmacol, Kodaira, Tokyo 1878502, Japan
[3] Juntendo Univ, Grad Sch Med, Dept Psychiat & Behav Sci, Tokyo 1138421, Japan
[4] Univ Tsukuba, Fac Med, Dept Neurol, Tsukuba, Ibaraki 3058575, Japan
关键词
Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; Mutation; Proteasome; TDP-43; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; DNA-BINDING PROTEIN-43; C-TERMINAL FRAGMENTS; TARDBP MUTATIONS; STRESS GRANULES; SQSTM1; MUTATIONS; MOTOR DEFICITS; RICH REGION; ALS;
D O I
10.1007/s12035-014-8644-6
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
TAR DNA-binding protein (TDP-43) is a major component of most ubiquitin-positive neuronal and glial inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of missense mutations in the TARDBP gene have been identified in patients with familial and sporadic ALS, as well as familial FTLD with ALS. In the diseased states, TDP-43 proteins exhibit characteristic alterations, including truncation, abnormal phosphorylation, and altered subcellular distribution. However, the mechanisms by which TDP-43 mutations induce neurodegeneration remain unclear at present. In the current study, we analyzed protein turnover and subcellular distribution of wild-type TDP-43 and two disease-associated mutants (G298S and A382T) in human neuroblastoma SH-SY5Y cells stably expressing TDP-43 with a C-terminal tag. Cycloheximide chase experiments revealed more rapid turnover of TDP-43 mutant proteins than their wildtype counterpart. The decrease in the TDP-43 level after cycloheximide treatment was partially recovered upon co-treatment with the proteasome inhibitor, epoxomicin, but not the lysosomotropic agent, chloroquine, suggesting involvement of the proteasomal pathway in TDP-43 degradation. Analysis of the subcellular distribution of TDP-43 revealed predominant localization in the nuclear fraction, whereas the relative level in the cytoplasm remained unaltered in cells expressing either mutant protein, compared with wild-type protein. Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy.
引用
收藏
页码:1049 / 1058
页数:10
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