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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


Objectives:
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)
9:00-9:45
Neurodegenerative diseases: diverse mechanisms, diverse disorders
 
Henry Paulson
10:00-10:45
Potential of imaging for CNS disorders
 
Nicole Deglon
11:00-11:45 
Polyglutamine neurodegeneration: overview of mechanisms
 
Henry Paulson
14:30-15:00 
Polyglutamine disorders: A structural perspective
 
Sandra Ribeiro
 
 
Tuesday (Dec 13)
9:00-10:00
HD: common lessons from a unique disease
 
Henry Paulson
10:15-11:15
Mouse models of Huntington´s disease
 
Maria Björkqvist
14:30-15:30
Viral-based animal models of polyglutamine disorders
 
Nicole Deglon
15:45-16:45
Hypothalamic pathology in Huntington´s disease
 
Maria Björkqvist
 
 
Wednesday (Dec14)
9:00-10:00 
Endocrine changes in Huntington´s disease
 
Maria Björkqvist
10:00-10:30
Mitochondrial dysfunction and excitotoxicity in Huntington’s disease
 
A. Cristina Rego
14:30-15:30
SCA3: linking protein quality control and polyQ pathogenesis
 
Henry Paulson
15:30-16:00
Nuclear translocation of ataxin-3
 
Ana Luisa Carvalho
16:15-17:00
Genetics of polyglutamine disorders
 
Patrícia Maciel
 
 
Thursday (Dec 15)
9:00-10:00 
Gene transfer approaches for Huntington´s disease
 
Nicole Deglon
10:15-11:15
RNAi as potential therapy
 
Henry Paulson
14:30-15:00
Lentiviral-based ataxin-3 gene expression and silencing
 
Luís Pereira de Almeida
15:00-17:00 
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)
9:00-11:00
Reading assignments:
 
 
Students presenting: Lígia Gomes, Joana Lourenço
 
 
 
 
Students presenting: Mariana Bexiga, Sofia Domingues
 
 
 
 
Students presenting: Ricardo Soares, Gisela Silva
 
 
11:00-12:00
Discussion of ‘hot-topics’
16:00-17:00
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.
 
 
Coordinators
 
 
 
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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