A molecular mechanism underlying the neural-specific defect in torsinA mutant mice

Connie E. Kim, Alex Perez, Guy Perkins, Mark H. Ellisman, William T. Dauer

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion ("ΔE") in the widely expressed gene TOR1A. Disease mutant knockin mice (Tor1a ΔE/ΔE) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in Tor1a ΔE/ΔE nonneuronal cells. The Tor1a ΔE/ΔE neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.

Original languageEnglish (US)
Pages (from-to)9861-9866
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number21
DOIs
StatePublished - May 25 2010
Externally publishedYes

Fingerprint

Nuclear Envelope
Organ Specificity
Dystonic Disorders
RNA Interference
Phenotype
Neurons
Peptides
Genes

Keywords

  • Dystonia
  • DYT1
  • LAP1
  • Nuclear envelope

ASJC Scopus subject areas

  • General

Cite this

A molecular mechanism underlying the neural-specific defect in torsinA mutant mice. / Kim, Connie E.; Perez, Alex; Perkins, Guy; Ellisman, Mark H.; Dauer, William T.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 21, 25.05.2010, p. 9861-9866.

Research output: Contribution to journalArticle

@article{8030f8dd1ca24f0c92611b658136a5a7,
title = "A molecular mechanism underlying the neural-specific defect in torsinA mutant mice",
abstract = "A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion ({"}ΔE{"}) in the widely expressed gene TOR1A. Disease mutant knockin mice (Tor1a ΔE/ΔE) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in Tor1a ΔE/ΔE nonneuronal cells. The Tor1a ΔE/ΔE neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.",
keywords = "Dystonia, DYT1, LAP1, Nuclear envelope",
author = "Kim, {Connie E.} and Alex Perez and Guy Perkins and Ellisman, {Mark H.} and Dauer, {William T.}",
year = "2010",
month = "5",
day = "25",
doi = "10.1073/pnas.0912877107",
language = "English (US)",
volume = "107",
pages = "9861--9866",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "21",

}

TY - JOUR

T1 - A molecular mechanism underlying the neural-specific defect in torsinA mutant mice

AU - Kim, Connie E.

AU - Perez, Alex

AU - Perkins, Guy

AU - Ellisman, Mark H.

AU - Dauer, William T.

PY - 2010/5/25

Y1 - 2010/5/25

N2 - A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion ("ΔE") in the widely expressed gene TOR1A. Disease mutant knockin mice (Tor1a ΔE/ΔE) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in Tor1a ΔE/ΔE nonneuronal cells. The Tor1a ΔE/ΔE neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.

AB - A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion ("ΔE") in the widely expressed gene TOR1A. Disease mutant knockin mice (Tor1a ΔE/ΔE) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in Tor1a ΔE/ΔE nonneuronal cells. The Tor1a ΔE/ΔE neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.

KW - Dystonia

KW - DYT1

KW - LAP1

KW - Nuclear envelope

UR - http://www.scopus.com/inward/record.url?scp=77953090863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953090863&partnerID=8YFLogxK

U2 - 10.1073/pnas.0912877107

DO - 10.1073/pnas.0912877107

M3 - Article

C2 - 20457914

AN - SCOPUS:77953090863

VL - 107

SP - 9861

EP - 9866

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 21

ER -