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Neurodegenerative Disorders
December 12 - 16
Coordinators: A. Cristina Rego and Luís Pereira de Almeida

Invited Lecturers:
Henry L. Paulson (MD, PhD), Associate Professor - Department of Neurology, Carver College of Medicine, University of Iowa, 200 Hawkins Dr ., Iowa City , IA 52242, U.S.A. Tel: +319-356-8758; Fax: +319-356-4505
Nicole Deglon (PhD) - Atomic Energy Commission (CEA), Department of Medical Research and ImaGene Program, Service Hospitalier Frédéric Joliot, 4, Place du Général Leclerc, 91401 Orsay Cedex; Phone: +33 1 69 08 62 14 or 37 32; Fax: +33 1 69 86 77 45
Maria Björkqvist (PhD) - Department of Experimental Medical Sciences, Section for Neuronal Survival, BMC A10, Section for Molecular Metabolism, BMC C11, SE-221 84 LUND; telephon: +46-46 222 9796; http://www.nesu.mphy.lu.se/
Ana Luísa Carvalho (PhD) - Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal
Patrícia Maciel (PhD) - Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Gualtar Campus, 4710-057 Braga.
Sandra Ribeiro (PhD) - Center for Neuroscience and Cell Biology, Edifício IBILI, 3rd Floor, Azinhaga de Sta. Comba, Celas, Coimbra, Portugal

Specific title: Polyglutamine expansion diseases

This course will focus on the latest research in the field of the polyglutamine diseases, which are caused by triplet repeat mutations consisting of CAG expansions within the coding regions of specific proteins. These disorders affect selective brain regions and exhibit a gradual progression of symptoms that finally result in the death of the patients. Although the genetic defects have been established, the mechanism(s) by which the mutant protein(s) initiates the specific pathogenic process for each disease remains to be elucidated. Thus, this course is intended to promote the understanding of molecular mechanisms operating in these diseases, which are also common to other neurodegenerative diseases. Furthermore, some of these disorders are the current focus of research by several groups at the CNC.

Course Schedule
Monday (Dec 12)
Neurodegenerative diseases: diverse mechanisms, diverse disorders
Henry Paulson
Potential of imaging for CNS disorders
Nicole Deglon
Polyglutamine neurodegeneration: overview of mechanisms
Henry Paulson
Polyglutamine disorders: A structural perspective
Sandra Ribeiro
Tuesday (Dec 13)
HD: common lessons from a unique disease
Henry Paulson
Mouse models of Huntington´s disease
Maria Björkqvist
Viral-based animal models of polyglutamine disorders
Nicole Deglon
Hypothalamic pathology in Huntington´s disease
Maria Björkqvist
Wednesday (Dec14)
Endocrine changes in Huntington´s disease
Maria Björkqvist
Mitochondrial dysfunction and excitotoxicity in Huntington’s disease
A. Cristina Rego
SCA3: linking protein quality control and polyQ pathogenesis
Henry Paulson
Nuclear translocation of ataxin-3
Ana Luisa Carvalho
Genetics of polyglutamine disorders
Patrícia Maciel
Thursday (Dec 15)
Gene transfer approaches for Huntington´s disease
Nicole Deglon
RNAi as potential therapy
Henry Paulson
Lentiviral-based ataxin-3 gene expression and silencing
Luís Pereira de Almeida
Reading assignments:
Students presenting: Catarina Pimentel, Eduardo Ferreira
Students presenting: Ana C. Cristovão, Ricardo Marques
Students presenting: Ana I. Teles, Carina Santos
Friday (Dec 16)
Reading assignments:
Students presenting: Lígia Gomes, Joana Lourenço
Students presenting: Mariana Bexiga, Sofia Domingues
Students presenting: Ricardo Soares, Gisela Silva
Discussion of ‘hot-topics’
Seminar: Toward understanding pathogenesis of Machado-Joseph disease
Henry L. Paulson

Complementary reading

Publications of invited speakers and coordinators

Invited speakers
Henry L. Paulson
Miller VM, Nelson RF, Gouvion CM, Williams A, Rodriguez-Lebron E, Harper SQ, Davidson BL, Rebagliati MR, Paulson HL (2005) CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci.. 25:9152-9161.
Chai Y, Berke SS, Cohen RE, Paulson HL. Poly-ubiquitin binding by the polyQ disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 2003; 279(5):3605-3611.
Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM, Paulson HL, Davidson BL (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington´s disease mouse model. Proc Natl Acad Sci U S A. 102: 5820-5825.
Nicole Deglon
Deglon N, Hantraye P (2005) Viral vectors as tools to model and treat neurodegenerative disorders.J Gene Med. 7: 530-539. Review.
Zala, D., Benchoua, A., Brouillet, E., Perrin, V., Gaillard, M. C., Zurn, A. D., Aebischer, P., Déglon, N. (2005). Progressive and selective striatal degeneration in primary neuronal cultures using lentiviral vector coding for a mutant huntingtin fragment. Neurobiol. Dis. (In Press).
Régulier, E., Trottier, Y., Perrin, V., Aebischer, P., Déglon N. (2003). Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum. Hum. Mol. Genet. 12: 2827-2836.
Maria Björkqvist
Petersén Å, Gil J, Maat-Schieman, Björkqvist M, Tanila H, Araújo IM, Smith R, Popovic N, Wierup N, Norlén P, Li J.-Y, Roos RAC, Sundler F, Mulder H and Brundin P. (2005) Orexin loss in Huntington’s disease. Hum Mol Gen 14:1-9. [Commentary by: Khamsi, Nature 432: 288 (2005); and by Hurtley, Science 307:483 (2005)].
Björkqvist M, Fex M, Renström E, Wierup N, Petersén Å, Gil J, Bacos K, Popovic N, Li Y-J, Sundler F, Brundin P, Mulder H. The R6/2 transgenic mouse model of Huntington’s disease develops diabetes due to deficient b-cell mass and exocytosis. Hum Mol Gen 14: 565-574 (2005)
Papalexi E, Persson A, Björkqvist M, Petersén Å, Woodman B, Bates G.P, Sundler F, Mulder H, Brundin P, Popovic N. (2005) Reduction of GnRH causes infertility in  the R6/2 mouse model of Huntington’s disease. Eur J Neurosci. 22:1541-1546.
Ana Luísa Carvalho
Correia SS, Duarte CB, Faro CJ, Pires EV, Carvalho AL Protein kinase C gamma associates directly with the GluR4 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit. Effect on receptor phosphorylation. J Biol Chem. 2003.
Carvalho AL, Correia S, Faro CJ, Duarte CB, Carvalho AP, Pires EM Phosphorylation of GluR4 AMPA-type glutamate receptor subunit by protein kinase C in cultured retina amacrine neurons. Eur J Neurosci. 2002 Feb;15(3):465-74.
Patrícia Maciel (PhD)
do Carmo Costa M, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, Sequeiros J, Maciel P Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics. 2005 Dec;6(4):209-15.
do Carmo Costa M, Gomes-da-Silva J, Miranda CJ, Sequeiros J, Santos MM, Maciel P Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado-Joseph disease (MJD) gene. Genomics. 2004 Aug;84(2):361-73.
Sandra Ribeiro (PhD)
Gales L, Cortes L, Almeida C, Melo CV, do Carmo Costa M, Maciel P, Clarke DT, Damas AM, Macedo-Ribeiro SJ Mol Biol. 2005 Oct 28;353(3):642-54. Towards a structural understanding of the fibrillization pathway in Machado-Joseph´s disease: trapping early oligomers of non-expanded ataxin-3.
Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature. 1999 Nov 25;402(6760):434-9.
Duarte AI, Santos MS, Oliveira CR, Rego AC (2005) Insulin neuroprotection against oxidative stress in cortical neurons-Involvement of uric acid and glutathione antioxidant defenses. Free Radic Biol Med. 39: 876-889.
Almeida S, Domingues A, Rodrigues L, Oliveira CR, Rego AC (2004) FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures. Neurobiol Dis. 17: 435-444.
de Almeida LP, Ross CA, Zala D, Aebischer P, Deglon N (2002) Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J Neurosci. 22: 3473-3483.
de Lima MC, da Cruz MT, Cardoso AL, Simoes S, de Almeida LP (2005) Liposomal and viral vectors for gene therapy of the central nervous system. Curr Drug Targets CNS Neurol Disord. 4: 453-465. Review

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