Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

Sami J. Barmada; Andrea Serio; Arpana Arjun; Bilada Bilican; Aaron Daub; D. Michael Ando; Andrey Tsvetkov; Michael Pleiss; Xingli Li; Daniel Peisach; Christopher Shaw; Siddharthan Chandran; Steven Finkbeiner

doi:10.1038/nchembio.1563

Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

Sami J. Barmada, Andrea Serio, Arpana Arjun, Bilada Bilican, Aaron Daub, D. Michael Ando, Andrey Tsvetkov, Michael Pleiss, Xingli Li, Daniel Peisach, Christopher Shaw, Siddharthan Chandran, Steven Finkbeiner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

334 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	677-685
Number of pages	11
Journal	Nature Chemical Biology
Volume	10
Issue number	8
Early online date	29 Jun 2014
DOIs	https://doi.org/10.1038/nchembio.1563
Publication status	Published - Aug 2014

Keywords

AMYOTROPHIC-LATERAL-SCLEROSIS
INCLUSION-BODY FORMATION
SPINAL MOTOR-NEURONS
TDP-43 PROTEINOPATHIES
MOUSE MODEL
FRONTOTEMPORAL DEMENTIA
HUNTINGTONS-DISEASE
MUTANT HUNTINGTIN
CELL MODEL
DEATH

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nchembio.1563

Cite this

@article{26260dccbb084c2da1f83f9c23e48743,

title = "Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models",

abstract = "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.",

keywords = "AMYOTROPHIC-LATERAL-SCLEROSIS, INCLUSION-BODY FORMATION, SPINAL MOTOR-NEURONS, TDP-43 PROTEINOPATHIES, MOUSE MODEL, FRONTOTEMPORAL DEMENTIA, HUNTINGTONS-DISEASE, MUTANT HUNTINGTIN, CELL MODEL, DEATH",

author = "Barmada, {Sami J.} and Andrea Serio and Arpana Arjun and Bilada Bilican and Aaron Daub and Ando, {D. Michael} and Andrey Tsvetkov and Michael Pleiss and Xingli Li and Daniel Peisach and Christopher Shaw and Siddharthan Chandran and Steven Finkbeiner",

year = "2014",

month = aug,

doi = "10.1038/nchembio.1563",

language = "English",

volume = "10",

pages = "677--685",

journal = "Nature Chemical Biology",

issn = "1552-4450",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

AU - Barmada, Sami J.

AU - Serio, Andrea

AU - Arjun, Arpana

AU - Bilican, Bilada

AU - Daub, Aaron

AU - Ando, D. Michael

AU - Tsvetkov, Andrey

AU - Pleiss, Michael

AU - Li, Xingli

AU - Peisach, Daniel

AU - Shaw, Christopher

AU - Chandran, Siddharthan

AU - Finkbeiner, Steven

PY - 2014/8

Y1 - 2014/8

N2 - 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.

AB - 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.

KW - AMYOTROPHIC-LATERAL-SCLEROSIS

KW - INCLUSION-BODY FORMATION

KW - SPINAL MOTOR-NEURONS

KW - TDP-43 PROTEINOPATHIES

KW - MOUSE MODEL

KW - FRONTOTEMPORAL DEMENTIA

KW - HUNTINGTONS-DISEASE

KW - MUTANT HUNTINGTIN

KW - CELL MODEL

KW - DEATH

U2 - 10.1038/nchembio.1563

DO - 10.1038/nchembio.1563

M3 - Article

SN - 1552-4450

VL - 10

SP - 677

EP - 685

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 8

ER -

Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this