The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration

Cherry Cheng Ying Ho, Hardy J. Rideout, Elena Ribe, Carol M. Troy, William T. Dauer

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.

Original languageEnglish (US)
Pages (from-to)1011-1016
Number of pages6
JournalJournal of Neuroscience
Volume29
Issue number4
DOIs
StatePublished - Jan 28 2009
Externally publishedYes

Fingerprint

Fas-Associated Death Domain Protein
Caspase 8
Leucine
Parkinson Disease
Phosphotransferases
Cell Death
Missense Mutation
Transcriptional Activation
leucine-rich repeat proteins
Cause of Death
Alzheimer Disease
Mutation

Keywords

  • Apoptosis
  • Caspase
  • Neuron death
  • Neuronal apoptosis
  • Neuronal death
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. / Ho, Cherry Cheng Ying; Rideout, Hardy J.; Ribe, Elena; Troy, Carol M.; Dauer, William T.

In: Journal of Neuroscience, Vol. 29, No. 4, 28.01.2009, p. 1011-1016.

Research output: Contribution to journalArticle

@article{f58c136636f4428798eac8e9f07699db,
title = "The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration",
abstract = "Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.",
keywords = "Apoptosis, Caspase, Neuron death, Neuronal apoptosis, Neuronal death, Parkinson's disease",
author = "Ho, {Cherry Cheng Ying} and Rideout, {Hardy J.} and Elena Ribe and Troy, {Carol M.} and Dauer, {William T.}",
year = "2009",
month = "1",
day = "28",
doi = "10.1523/JNEUROSCI.5175-08.2009",
language = "English (US)",
volume = "29",
pages = "1011--1016",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "4",

}

TY - JOUR

T1 - The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration

AU - Ho, Cherry Cheng Ying

AU - Rideout, Hardy J.

AU - Ribe, Elena

AU - Troy, Carol M.

AU - Dauer, William T.

PY - 2009/1/28

Y1 - 2009/1/28

N2 - Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.

AB - Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.

KW - Apoptosis

KW - Caspase

KW - Neuron death

KW - Neuronal apoptosis

KW - Neuronal death

KW - Parkinson's disease

UR - http://www.scopus.com/inward/record.url?scp=59649089328&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59649089328&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.5175-08.2009

DO - 10.1523/JNEUROSCI.5175-08.2009

M3 - Article

C2 - 19176810

AN - SCOPUS:59649089328

VL - 29

SP - 1011

EP - 1016

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 4

ER -