Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington's disease molecular pathogenesis

Jason Miller, Montserrat Arrasate, Benjamin A. Shaby, Siddhartha Mitra, Eliezer Masliah, Steven Finkbeiner

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

An expanded polyglutamine (polyQ) stretch in the protein huntingtin (htt) induces self-aggregation into inclusion bodies (IBs) and causes Huntington's disease (HD). Defining precise relationships between early observable variables and neuronal death at the molecular and cellular levels should improve our understanding of HD pathogenesis. Here, we used an automated microscope that tracks thousands of neurons individually over their entire lifetime to quantify interconnected relationships between early variables, such as htt levels, polyQ length, and IB formation, and neuronal death in a primary striatal model of HD. The resulting model revealed that mutant htt increases the risk of death by tonically interfering with homeostatic coping mechanisms rather than producing accumulated damage to the neuron, htt toxicity is saturable, the rate-limiting steps for inclusion body formation and death can be traced to different conformational changes in monomeric htt, and IB formation reduces the impact of the starting levels of htt of a neuron on its risk of death. Finally, the model that emerges from our quantitative measurements places critical limits on the potential mechanisms by which mutant htt might induce neurodegeneration, which should help direct future research.

Original languageEnglish (US)
Pages (from-to)10541-10550
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number31
DOIs
StatePublished - Aug 4 2010

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington's disease molecular pathogenesis'. Together they form a unique fingerprint.

Cite this