The document summarizes Huntington's disease (HD), including that it is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. It describes the clinical features and progression of HD and discusses the role of mutant huntingtin. It also summarizes the pathology of HD in the brain and basal ganglia. Various animal models of HD are described, including toxin models, genetic mouse models expressing mutant huntingtin fragments or full-length protein, and non-human primate models.

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

4. In the brain, huntingtin is highly expressed in the cortex and moderately expressed in the striatum

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