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

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  • 1. Corea di Huntington: dalla neuropatologia clinica ai modelli animali
    Francesca R. Fusco & Marina Melone
  • 2. HUNTINGTON’S DISEASE
    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).
    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).
    Death typically occurs after 17 years of diagnosis for complications such as accidents, aspiration and dysphagia
  • 3. Role of huntingtin
    • The protein huntingtin is widespread in bodily tissues
    • 4. In the brain, huntingtin is highly expressed in the cortex and moderately expressed in the striatum
    • 5. Toxic gain of function vs. loss of function
  • • Formation of intranuclear inclusions of
    mutated huntingtin (DiFiglia et al., 1997).
    • Mitochondrial damage/ oxidative stress/Excitotoxicity
    • Deprivation of neurotrophic factors
    (BDNF)
    • Decreased anti-apoptotic factors
    LOSS OF FUNCTION
    GAIN OF FUNCTION
    PATHOPHYSIOLOGY OF HUNTINGTON’S DISEASE
  • 6. Huntington’s disease: the basal ganglia
    calbindin
    The basal ganglia comprise a set of subcortical brain structures involved in various aspects of motor control and cognition
  • 7. Huntington’s disease brain pathology
  • 8. Huntington’s disease brain pathology- grading
  • 9. Huntington’s disease brain pathology
    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
    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
    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)
  • 10. Huntingtin inclusions:
    Intranuclear
    Cytoplasmic
    Distrophic neurites
    NIs are all ubiquinated
  • 11. Ubiquitinated inclusions also contain:
    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)
    CREB-binding protein (CBP)in NIIs (Giampà et al, 2009)
  • 12. Neuronal cell types affected in HD
    At the cellular level, HD is characterized by differential vulnerability of specific neuronal subpopulation within striatum and cortex
  • 13. Marker
    Cell type
    Survival in HD
    CALB
    spiny projection
    majority die
    large aspiny
    interneurons
    survive
    ChAT
    survive
    medium aspiny
    interneurons
    NOS
    PARV
    large aspiny
    interneurons
    majority die
    CALR
    medium aspiny
    interneurons
    majority die
  • 14. Marker
    Projection target
    Survival in HD
    GPe
    SP
    “indirect pathway”
    GPi, SN
    Die slowly
    ENK
    “direct pathway”
    STRIATAL PROJECTION NEURONS
    Choreic movements are associated with the early degeneration of the indirect pathway
    Rigidity and bradykinesia are the manifestations of degeneration of the direct pathway
  • 15. Causes of neuronal vulnerability
    Cellular Localization of Huntingtin in Striatal and Cortical Neurons
    in Rats: Lack of Correlation with Neuronal Vulnerability in
    Huntington’s Disease
    Francesca R. Fusco,1 Quan Chen,1 William J. Lamoreaux,2 Griselle Figueredo-Cardenas,1 Yun Jiao,1
    Jonathan A. Coffman,1 D. James Surmeier,3 Marcia G. Honig,1 Leon R. Carlock,4 and Anton Reiner1
    1Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee–Memphis, The Health
    Sciences Center, Memphis, Tennessee 38163, 2Department of Biology, College of Staten Island, City University of New
    York, Staten Island, New York 10314, 3Department of Physiology/Northwestern University Institute for Neuroscience,
    Searle 5–474, Northwestern University Medical School, Chicago, Illinois 60611, and 4Department of Molecular Biology
    and Genetics, School of Medicine, Wayne State University, Detroit, Michigan 48201
    Striatal neurons and thir content in Huntingtin
    Cholinergic interneuron 99.0% Survive
    SS/NPY/NOS interneuron 1.9% Survive
    PARV interneuron 17.8% Majority die
    Matrix projection neuron 63.8% Majority die
    Cortical neurons
    Layer 5 corticostriatal projection neuron 100.0% Some die
  • 16. HD Models
    Toxin models: 1- excitotoxic lesions in animals
    2- defective energy metabolism models
    Genetic models: 1- Fragment/segment genetic murine models of human HD (R6/2, R6/1, N171-82Q)
    2- Murine huntingtin homologue knock-in mice (Hdh/Q72–80, HdhQ111, CAG140, CAG150)
    3-Full-length human HD gene transgenic mouse models
    Non-human primate models of HD
  • 17. QUINOLINIC ACID LESIONS
    • INTRASTRIATAL INJECTION BY STEREOTAXIC APPARATUS
    • EXCITOTOXIC STRIATAL NEURONAL DEATH RECAPITULATES HD PATHOLOGY
  • 18. Histology of QA lesions
    500µm
    500µm
    Giampà et al, 2008
  • 19. Rat 3-NP Lesions
  • 20. HD Genetic models: fragment models
    From RJ FErrante, 2009
  • 21. Gross anatomy of R6/2
    Giampà et al, 2010
  • 22. Histology of R6/2
    NIIs
    De March et al, 2009
  • 23. Histology of R6/2
    Reactive Microglia
    Giampa’ et al, 2010
  • 24. HD genetic models: Knock-in models
    From RJ FErrante, 2009
  • 25. HD genetic models: Human full length
    YAC128 (yeast artificial chromosome)
    BAC (bacterial artificial chromosome)
    transgenic RAT
  • 26. HD genetic models: Human full length
    YAC128 (yeast artificial chromosome)
    Wang et al.Molecular Neurodegeneration 2010
  • 27. HD genetic models: Human full length
    BAC
    Critteden et al, 2010 Hum. Mol. Genetics
  • 28. other models
    GFAP-HD mouse (Bradford et al, 2009)
    Non-human primate models
  • 29. HD animal models: A glimpse at our data
    QA Surgical model
  • 30. HD animal models: A glimpse at our data
    R6/2 Mouse model
    RAGE
    Giampà et al. submitted
  • 31. HD sucks