Noninvasive measurement of protein aggregation by mutant huntingtin fragments or α-synuclein in the lens

Paul J. Muchowski, Richard Ramsden, Quangvu Nguyen, Ernest E. Arnett, Teri Greiling, Susan K. Anderson, John I. Clark

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed post-mortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or α-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, αB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of αB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

Original languageEnglish (US)
Pages (from-to)6330-6336
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number10
DOIs
StatePublished - Mar 7 2008
Externally publishedYes

Fingerprint

Synucleins
Mutant Proteins
Lenses
Agglomeration
Proteins
Crystallins
Huntington Disease
Amyloid
Parkinson Disease
Crystalline Lens
Inborn Genetic Diseases
Prions
Brain Diseases
Cataract
Transgenic Mice
Alzheimer Disease
Brain
Imaging techniques

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Noninvasive measurement of protein aggregation by mutant huntingtin fragments or α-synuclein in the lens. / Muchowski, Paul J.; Ramsden, Richard; Nguyen, Quangvu; Arnett, Ernest E.; Greiling, Teri; Anderson, Susan K.; Clark, John I.

In: Journal of Biological Chemistry, Vol. 283, No. 10, 07.03.2008, p. 6330-6336.

Research output: Contribution to journalArticle

Muchowski, Paul J. ; Ramsden, Richard ; Nguyen, Quangvu ; Arnett, Ernest E. ; Greiling, Teri ; Anderson, Susan K. ; Clark, John I. / Noninvasive measurement of protein aggregation by mutant huntingtin fragments or α-synuclein in the lens. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 10. pp. 6330-6336.
@article{d2da62d5d4c547e5bccf6921d9bcc450,
title = "Noninvasive measurement of protein aggregation by mutant huntingtin fragments or α-synuclein in the lens",
abstract = "Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed post-mortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or α-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, αB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of αB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.",
author = "Muchowski, {Paul J.} and Richard Ramsden and Quangvu Nguyen and Arnett, {Ernest E.} and Teri Greiling and Anderson, {Susan K.} and Clark, {John I.}",
year = "2008",
month = "3",
day = "7",
doi = "10.1074/jbc.M709678200",
language = "English (US)",
volume = "283",
pages = "6330--6336",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - Noninvasive measurement of protein aggregation by mutant huntingtin fragments or α-synuclein in the lens

AU - Muchowski, Paul J.

AU - Ramsden, Richard

AU - Nguyen, Quangvu

AU - Arnett, Ernest E.

AU - Greiling, Teri

AU - Anderson, Susan K.

AU - Clark, John I.

PY - 2008/3/7

Y1 - 2008/3/7

N2 - Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed post-mortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or α-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, αB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of αB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

AB - Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed post-mortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or α-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, αB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of αB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

UR - http://www.scopus.com/inward/record.url?scp=44449119580&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44449119580&partnerID=8YFLogxK

U2 - 10.1074/jbc.M709678200

DO - 10.1074/jbc.M709678200

M3 - Article

C2 - 18167346

AN - SCOPUS:44449119580

VL - 283

SP - 6330

EP - 6336

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 10

ER -