Presentazione Fusco Fr - Melone-M.A.B.


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Presentazione Fusco Fr - Melone-M.A.B.

  1. 1. Corea di Huntington: dalla neuropatologia clinica ai modelli animali<br />Francesca R. Fusco & Marina Melone <br />
  2. 2. HUNTINGTON’S DISEASE<br />Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor dysfunction, cognitive decline and emotional and psychiatric disorder (Wilson et al., 1987; de la Monte et al., 1988).<br />The mutation involves the IT15 gene (The Huntington’s Disease Collaborative Research Group 1993) encoding for the protein Huntingtin, and is characterized by a CAG expansion beyond the normal 10–35 repeat range (Albin & Tagle, 1995).<br /> Death typically occurs after 17 years of diagnosis for complications such as accidents, aspiration and dysphagia<br />
  3. 3. Role of huntingtin<br /><ul><li>The protein huntingtin is widespread in bodily tissues
  4. 4. In the brain, huntingtin is highly expressed in the cortex and moderately expressed in the striatum
  5. 5. Toxic gain of function vs. loss of function</li></li></ul><li>• Formation of intranuclear inclusions of <br />mutated huntingtin (DiFiglia et al., 1997).<br />• Mitochondrial damage/ oxidative stress/Excitotoxicity <br />• Deprivation of neurotrophic factors <br />(BDNF)<br />• Decreased anti-apoptotic factors<br />LOSS OF FUNCTION<br />GAIN OF FUNCTION<br />PATHOPHYSIOLOGY OF HUNTINGTON’S DISEASE<br />
  6. 6. Huntington’s disease: the basal ganglia<br />calbindin<br />The basal ganglia comprise a set of subcortical brain structures involved in various aspects of motor control and cognition<br />
  7. 7. Huntington’s disease brain pathology<br />
  8. 8. Huntington’s disease brain pathology- grading<br />
  9. 9. Huntington’s disease brain pathology<br />There is a topographic progression of neuronal loss and astrogliosis rst observed in the dorso-medial aspect of the striatum and progressing ventro-laterally, with relative sparing of the ventral striatum<br />The striosomal/matrix pattern in the neostriatum is topographically altered in HD, with the total area of matrix reduced and the area of the striosomes unchanged<br /> Mutated huntingtin aggregates (NIIs, cytoplasmic) are largely confined to the cortex in patients, with very little localiaztion in the striatum (cytoprotective mechanism inactivating polyglutamine-induced neurotoxicity by sequestering the mutant protein until ubiquitination can dismantle it)<br />
  10. 10. Huntingtin inclusions:<br />Intranuclear<br />Cytoplasmic<br />Distrophic neurites<br />NIs are all ubiquinated<br />
  11. 11. Ubiquitinated inclusions also contain:<br />Transactivation-responsive DNA-binding protein 43 (TDP-43)in DN and cytoplasmic and DNs inclusions(Schwab et al, 2008), a protein that is present in inclusions of other neurodegenerative disorders such ALS (Giordana et al, 2009)<br />CREB-binding protein (CBP)in NIIs (Giampà et al, 2009)<br />
  12. 12. Neuronal cell types affected in HD<br />At the cellular level, HD is characterized by differential vulnerability of specific neuronal subpopulation within striatum and cortex<br />
  13. 13. Marker<br />Cell type<br />Survival in HD<br />CALB<br />spiny projection<br />majority die<br />large aspiny <br />interneurons<br />survive<br />ChAT<br />survive<br />medium aspiny<br /> interneurons<br />NOS<br />PARV<br />large aspiny <br />interneurons<br />majority die<br />CALR<br />medium aspiny<br /> interneurons<br />majority die<br />
  14. 14. Marker<br />Projection target<br />Survival in HD<br />GPe<br />SP<br />“indirect pathway”<br />GPi, SN<br />Die slowly<br />ENK<br />“direct pathway”<br />STRIATAL PROJECTION NEURONS<br />Choreic movements are associated with the early degeneration of the indirect pathway<br />Rigidity and bradykinesia are the manifestations of degeneration of the direct pathway<br />
  15. 15. Causes of neuronal vulnerability<br />Cellular Localization of Huntingtin in Striatal and Cortical Neurons<br />in Rats: Lack of Correlation with Neuronal Vulnerability in<br />Huntington’s Disease<br />Francesca R. Fusco,1 Quan Chen,1 William J. Lamoreaux,2 Griselle Figueredo-Cardenas,1 Yun Jiao,1<br />Jonathan A. Coffman,1 D. James Surmeier,3 Marcia G. Honig,1 Leon R. Carlock,4 and Anton Reiner1<br />1Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee–Memphis, The Health<br />Sciences Center, Memphis, Tennessee 38163, 2Department of Biology, College of Staten Island, City University of New<br />York, Staten Island, New York 10314, 3Department of Physiology/Northwestern University Institute for Neuroscience,<br />Searle 5–474, Northwestern University Medical School, Chicago, Illinois 60611, and 4Department of Molecular Biology<br />and Genetics, School of Medicine, Wayne State University, Detroit, Michigan 48201<br />Striatal neurons and thir content in Huntingtin<br />Cholinergic interneuron 99.0% Survive<br />SS/NPY/NOS interneuron 1.9% Survive<br />PARV interneuron 17.8% Majority die<br /> Matrix projection neuron 63.8% Majority die<br />Cortical neurons<br />Layer 5 corticostriatal projection neuron 100.0% Some die<br />
  16. 16. HD Models<br />Toxin models: 1- excitotoxic lesions in animals<br /> 2- defective energy metabolism models<br />Genetic models: 1- Fragment/segment genetic murine models of human HD (R6/2, R6/1, N171-82Q)<br /> 2- Murine huntingtin homologue knock-in mice (Hdh/Q72–80, HdhQ111, CAG140, CAG150)<br /> 3-Full-length human HD gene transgenic mouse models<br />Non-human primate models of HD<br />
  18. 18. Histology of QA lesions<br />500µm<br />500µm<br />Giampà et al, 2008<br />
  19. 19. Rat 3-NP Lesions<br />
  20. 20. HD Genetic models: fragment models<br />From RJ FErrante, 2009<br />
  21. 21. Gross anatomy of R6/2<br />Giampà et al, 2010<br />
  22. 22. Histology of R6/2<br />NIIs<br />De March et al, 2009<br />
  23. 23. Histology of R6/2<br />Reactive Microglia<br />Giampa’ et al, 2010<br />
  24. 24. HD genetic models: Knock-in models<br />From RJ FErrante, 2009<br />
  25. 25. HD genetic models: Human full length<br />YAC128 (yeast artificial chromosome)<br />BAC (bacterial artificial chromosome)<br />transgenic RAT <br />
  26. 26. HD genetic models: Human full length<br />YAC128 (yeast artificial chromosome)<br />Wang et al.Molecular Neurodegeneration 2010<br />
  27. 27. HD genetic models: Human full length<br />BAC<br />Critteden et al, 2010 Hum. Mol. Genetics<br />
  28. 28. other models<br />GFAP-HD mouse (Bradford et al, 2009)<br />Non-human primate models<br />
  29. 29. HD animal models: A glimpse at our data<br />QA Surgical model<br />
  30. 30. HD animal models: A glimpse at our data<br />R6/2 Mouse model<br />RAGE<br />Giampà et al. submitted<br />
  31. 31. HD sucks<br />