Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

被引：357

作者：

Barmada, Sami J. ^{[1
,2
,3
]}

Serio, Andrea ^{[4
,5
,6
,7
,8
]}

Arjun, Arpana ^{[1
]}

Bilican, Bilada ^{[4
,5
]}

Daub, Aaron ^{[1
]}

Ando, D. Michael ^{[1
,9
]}

Tsvetkov, Andrey ^{[1
,10
]}

Pleiss, Michael ^{[11
]}

Li, Xingli ^{[3
]}

Peisach, Daniel ^{[3
]}

Shaw, Christopher ^{[12
]}

Chandran, Siddharthan ^{[4
,5
]}

Finkbeiner, Steven ^{[1
,2
,9
,11
,13
,14
,15
,16
]}

机构：

[1] Gladstone Inst Neurol Dis, San Francisco, CA 94141 USA

[2] Univ Calif San Francisco, Med Ctr, Dept Neurol, San Francisco, CA 94143 USA

[3] Univ Michigan, Dept Neurol, Ann Arbor, MI USA

[4] Univ Edinburgh, Euan MacDonald Ctr Motor Neurone Dis Res, Edinburgh, Midlothian, Scotland

[5] Univ Edinburgh, Ctr Regenerat Med, MRC, Edinburgh, Midlothian, Scotland

[6] Univ London Imperial Coll Sci Technol & Med, Dept Mat, London, England

[7] Univ London Imperial Coll Sci Technol & Med, Dept Bioengn, London, England

[8] Univ London Imperial Coll Sci Technol & Med, Inst Biomed Engn, London, England

[9] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA

[10] Univ Texas Houston, Sch Med, Dept Neurobiol & Anat, Houston, TX 77225 USA

[11] Gladstone Inst, Keck Program Brain Cell Engn, San Francisco, CA USA

[12] Kings Coll London, Inst Psychiat, London WC2R 2LS, England

[13] Univ Calif San Francisco, Dept Physiol, San Francisco, CA USA

[14] Taube Koret Ctr Neurodegenerat Dis Res, San Francisco, CA USA

[15] Hellman Family Fdn Alzheimers Dis Res Program, San Francisco, CA USA

[16] Roddenberry Stem Cell Program, San Francisco, CA USA

来源：

NATURE CHEMICAL BIOLOGY | 2014年 / 10卷 / 08期

基金：

美国国家卫生研究院;

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; INCLUSION-BODY FORMATION; SPINAL MOTOR-NEURONS; MOUSE MODEL; MUTANT HUNTINGTIN; TDP-43; DISEASE; DEATH; PROTEINOPATHIES; DEGRADATION;

D O I：

10.1038/nchembio.1563

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology-cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause disease even if TDP43 lacks a mutation. Here we show that individual neurons vary in their ability to clear TDP43 and are exquisitely sensitive to TDP43 levels. To measure TDP43 clearance, we developed and validated a single-cell optical method that overcomes the confounding effects of aggregation and toxicity and discovered that pathogenic mutations shorten TDP43 half-life. New compounds that stimulate autophagy improved TDP43 clearance and localization and enhanced survival in primary murine neurons and in human stem cell-derived neurons and astrocytes harboring mutant TDP43. These findings indicate that the levels and localization of TDP43 critically determine neurotoxicity and show that autophagy induction mitigates neurodegeneration by acting directly on TDP43 clearance.

引用

页码：677 / U119

页数：11

共 50 条

[1]

Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].