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 M. Greiling, Susan K. Anderson, John I. Clark

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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