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Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation
Huntington's disease: from molecular pathogenesis to clinical treatment
Protein aggregation and neurodegenerative disease
There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin.
Transgenic mice that express a cDNA encoding an N-terminal fragment of huntingtin with 82, 44 or 18 glutamines develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely, consistent with the idea that N-Terminal fragments of Huntington's disease with a repeat expansion are toxic to neurons, and that N.terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.
Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity
It is found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain, suggesting polyglUTamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutsamine disorders.
A huntingtin-associated protein enriched in brain with implications for pathology
The identification of a protein (huntingtin-associated protein (HAP)-l) that binds to huntingtin is reported, enhanced by an expanded polyglutamine repeat, the length of which is also known to correlate with the age of disease onset19–21.
Kinase activity of mutant LRRK2 mediates neuronal toxicity
- Wanli W. Smith, Z. Pei, Haibing Jiang, V. Dawson, T. Dawson, C. Ross
- BiologyNature Neuroscience
- 1 October 2006
It is found that L RRK2 kinase activity was regulated by GTP via the intrinsic GTPase Roc domain, and alterations of LRRK2 protein that reduced kinaseactivity of mutant LRRk2 correspondingly reduced neuronal toxicity.
A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development
It is demonstrated that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics and suggesting that loss of DISC 1 function may underlie neurodevelopmental dysfunction in schizophrenia.
Detection of Huntington’s disease decades before diagnosis: the Predict-HD study
- Jane S. Paulsen, D. Langbehn, M. Hayden
- Medicine, PsychologyJournal of Neurology, Neurosurgery, and…
- 20 December 2007
The findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.