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Huntington’s Disease

Huntington’s Disease. Physiopathology and Phenotype. Borbála Szepes Kevin Pommier. Nantes, 15 th of September 2014. What is HD ?. n eurodegenerative genetic disorder of the CNS a lso known as Huntington chorea a utosomic d ominant mutation t rinucleotid e repeat disorders (CAG)

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Huntington’s Disease

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  1. Huntington’sDisease Physiopathology and Phenotype BorbálaSzepes Kevin Pommier Nantes, 15th of September 2014

  2. What is HD ? • neurodegenerative genetic disorder of the CNS • also known as Huntington chorea • autosomic dominant mutation • trinucleotide repeat disorders (CAG) • dynamic mutation • anticipation phenomenon • complete penetrance • prevalence : 1/10 000

  3. Huntingtin protein • product of Huntington gene (chromosome4p16.3) • soluble protein of 3144 AA • ubiquitously present but highest concentration in CNS neurons • associated with various organelles • also found in neurites and synapses (associated with vesicular structures) • role of thepolyQregion +++:polymorphism of the gene can lead to variablenumbers of glutamine residues present in the protein • normal protein: 6-35 glutamine residues • abnormal: over 36 • Main functions : • embryonicdevelopment regulator • antiapoptotic • control BDNF production(↑ transcription) • axonal and vesicular transportHuntingtin and BDNF vesicle transport • synaptic activity

  4. Physiopathology

  5. Why is HD limited to neurons and particularly to striatal neurons? • highly debated phenomen, only theories! • neural presence: associated proteins • HIP-1: huntingtin's interactor protein • HAP-1: huntingtin's associated protein • important sign: chorea → malfunction of the striatum • anatomical background : basal ganglia • striatum : caudate nucleus + putamen inhibitory pathway • Htt promotes axonal BDNF transport from the cerebral cortex to the striatum • essential!, not produced by striatal neurons • mutant Htt → deficiency in BDNF-mediated signaling → striatal atrophy (90%!) → chorea • progressively affects other structures and pathways

  6. Classification • Adult HD (mean age of onset ~ 35-44 yrs) • 95 % of all cases • 3 stages • Juvenile HD (mean age of onset ~ infancy-20 yrs) • same genetical alteration different phenotype • differences: • stiffness, rigidity, seizures • no chorea! • more rapid progression • similarities: • dementia • psychological changes • neurogical damage

  7. “pre-clinical”

  8. References • http://omim.org/entry/143100?search=huntington%20disease&highlight=huntington%20disease • http://www.ncbi.nlm.nih.gov/books/NBK1305/ • http://www.dailymotion.com/video/xbx3e5_patrick-pla-la-maladie-de-huntingto_tech • https://web.stanford.edu/group/hopes/cgi-bin/wordpress/?p=3419 • http://www.intechopen.com/books/huntington-s-disease-core-concepts-and-current-advances/bdnf-in-huntington-s-disease-role-in-pathogenesis-and-treatment • https://www.youtube.com/watch?v=my-ONvDYqpI

  9. Any questions? Thank you for your attention!

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