Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking

Fiona M. Laird, Mohamed H Farah, Steven Ackerley, Ahmet Hoke, Nicholas J Maragakis, Jeffrey D Rothstein, John Griffin, Donald L. Price, Lee J Martin, Philip Chun Wong

Research output: Contribution to journalArticle

Abstract

Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, ∼5-10% are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150Glued causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150Glued. Neuronal expression of mutant, but not wild type, dynactin p150Glued causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150Glued mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.

Original languageEnglish (US)
Pages (from-to)1997-2005
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number9
DOIs
StatePublished - Feb 27 2008

Fingerprint

Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Motor Neurons
Muscle Spasticity
Muscular Atrophy
Autophagy
Missense Mutation
Neurodegenerative Diseases
Dynactin Complex
Mutation
Genes
Amyotrophic lateral sclerosis 1

Keywords

  • ALS
  • Autophagy
  • Dynactin
  • Motor neuron disease model
  • p150
  • Vesicular trafficking

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking. / Laird, Fiona M.; Farah, Mohamed H; Ackerley, Steven; Hoke, Ahmet; Maragakis, Nicholas J; Rothstein, Jeffrey D; Griffin, John; Price, Donald L.; Martin, Lee J; Wong, Philip Chun.

In: Journal of Neuroscience, Vol. 28, No. 9, 27.02.2008, p. 1997-2005.

Research output: Contribution to journalArticle

@article{739fde67adf84ae5a6c21ac735c2e294,
title = "Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking",
abstract = "Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, ∼5-10{\%} are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150Glued causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150Glued. Neuronal expression of mutant, but not wild type, dynactin p150Glued causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150Glued mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.",
keywords = "ALS, Autophagy, Dynactin, Motor neuron disease model, p150, Vesicular trafficking",
author = "Laird, {Fiona M.} and Farah, {Mohamed H} and Steven Ackerley and Ahmet Hoke and Maragakis, {Nicholas J} and Rothstein, {Jeffrey D} and John Griffin and Price, {Donald L.} and Martin, {Lee J} and Wong, {Philip Chun}",
year = "2008",
month = "2",
day = "27",
doi = "10.1523/JNEUROSCI.4231-07.2008",
language = "English (US)",
volume = "28",
pages = "1997--2005",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "9",

}

TY - JOUR

T1 - Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking

AU - Laird, Fiona M.

AU - Farah, Mohamed H

AU - Ackerley, Steven

AU - Hoke, Ahmet

AU - Maragakis, Nicholas J

AU - Rothstein, Jeffrey D

AU - Griffin, John

AU - Price, Donald L.

AU - Martin, Lee J

AU - Wong, Philip Chun

PY - 2008/2/27

Y1 - 2008/2/27

N2 - Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, ∼5-10% are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150Glued causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150Glued. Neuronal expression of mutant, but not wild type, dynactin p150Glued causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150Glued mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.

AB - Amyotrophic lateral sclerosis (ALS), a fatal and progressive neurodegenerative disorder characterized by weakness, muscle atrophy, and spasticity, is the most common adult-onset motor neuron disease. Although the majority of ALS cases are sporadic, ∼5-10% are familial, including those linked to mutations in SOD1 (Cu/Zn superoxide dismutase). Missense mutations in a dynactin gene (DCTN1) encoding the p150Glued subunit of dynactin have been linked to both familial and sporadic ALS. To determine the molecular mechanism whereby mutant dynactin p150Glued causes selective degeneration of motor neurons, we generated and characterized mice expressing either wild-type or mutant human dynactin p150Glued. Neuronal expression of mutant, but not wild type, dynactin p150Glued causes motor neuron disease in these animals that are characterized by defects in vesicular transport in cell bodies of motor neurons, axonal swelling and axo-terminal degeneration. Importantly, we provide evidence that autophagic cell death is implicated in the pathogenesis of mutant p150Glued mice. This novel mouse model will be instrumental for not only clarifying disease mechanisms in ALS, but also for testing therapeutic strategies to ameliorate this devastating disease.

KW - ALS

KW - Autophagy

KW - Dynactin

KW - Motor neuron disease model

KW - p150

KW - Vesicular trafficking

UR - http://www.scopus.com/inward/record.url?scp=39849107361&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39849107361&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4231-07.2008

DO - 10.1523/JNEUROSCI.4231-07.2008

M3 - Article

C2 - 18305234

AN - SCOPUS:39849107361

VL - 28

SP - 1997

EP - 2005

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 9

ER -