The PSP Association

Lead researcher Justo García de Yebenes
Co-researchers Dr Raquel Ros and Dr David Israel Ampuero

Institution Laboratorio de Biología Molecular, Fundación para Investigaciones Neurológicas, Facultad de Medicina, Universidad Complutense de Madrid, Spain, and PET Centre, Hammersmith Hospital, London

Duration
Start xxxx End xxxx:

Grant

Aim of research
To gain a better understanding of the genetic aspects of PSP in families.

About the research
Whilst not common, the number of reports of families where more than one member has been affected by PSP is increasing. In this study we investigated the molecular defects which produced PSP in a number of families with hereditary PSP, i.e., with multiple patients affected with this disease. Because the number of patients available for molecular testing in these families (even in the largest one - a family from Spain with 35 subjects available for investigation) was small for linkage analyses, we expanded the number of patients by detecting presymptomatic disease carriers with PET (positron emission tomography) techniques.

Findings
In familial PSP we found that at least three genes could be responsible for the disease. These genes were tau, parkin and a third as yet unknown gene located at chromosome 1, and different from the genes which produce Parkinson´s disease. Because we identified tau and parkin as important proteins in PSP we developed a double mutant mouse with changes in these two proteins which develops clinical and neuropathological symptoms similar to those seen in PSP. Using this mouse model we are now testing compounds which may halt or reverse the course of the disease.

What does the outcome of this research mean for people with PSP?
In this research we discovered several gene defects which may lead to the disease, a locus (one part of a chromosome were there is a gene responsible for it), and we created a mouse model which will allow us to conduct pharmacological studies. This work forms the foundation for the development of new drugs to treat PSP.

Publications arising from the work
Rojo A, Pernaute RS, Fontán A, Ruíz PG, Honnorat J, Lynch T, Chin S, Gonzalo I, Rábano A, Martínez A, Daniel S, Pramsteller P, Morris H, Wood N, Lees A, Tabernero C, Nyggard T, Jackson AC, Hanson A, García de Yébenes J. Clinical genetics of familial progressive supranuclear palsy. Brain. 1999. 122, 1233-1245.

Hoenicka J, Pérez M, Pérez-Tur J, Barabash A, Godoy M, Vidal L, Astarloa R, Avila J, Nygaard T, García de Yébenes J. The tau gene A0 allele and progressive supranuclear palsy. Neurology 1999. 53: 1219-1225.

Piccini P, Garcia de Yebenes J, Lees AJ, Ceravolo R, Turjanski N, Pramstaller P, Brooks DJ. Familial Progressive Supranuclear Palsy. Arch. Neurol. 2001. 58: 1846-1851.

Sánchez M, Gonzalo I, Avila J, García de Yébenes J. Progressive supranuclear palsy and tau hyperphosphorylation in a patient with a C212Y parkin mutation. J of Alzheimer´s Disease. 2002. 4: 399-404.

Itier JM, Ibañez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Sanchez M, Denèfle P, Benavides J, Tremp G, Rooney TA, Brice A, García de Yébenes J. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Human Molecular Genetics, 2003. 12 (8): 2277-2291.

Morales B, Martínez A, Gonzalo I, Vidal L, Ros R, Gómez-Tortosa E, Rábano A, Ampuero I, Sánchez M, Hoenicka J, García de Yébenes J. Steele-Richardson-Olszewski syndrome in a patient with a single C212Y mutation in the parkin protein. Movement Disorders 2002. 17(6): 1374-1380.

Ros R, Gomez Garre P, Hirano M, Tai YF, Ampuero I, Vidal L, Rojo A, Fontan A, Vazquez A, Fanjul S, Hernandez J, Cantarero S, Hoenicka J, Jones A, Ahsan RL, Pavese N, Piccini P, Brooks DJ, Perez-Tur J, Nyggard T, de Yebenes JG. Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1. Ann Neurol. 2005. 57(5):634-41.

Ros R, Thobois S, Streichenberger N, Kopp N, Sanchez MP, Perez M, Hoenicka J, Avila J, Honnorat J, de Yebenes JG. A New Mutation of the {tau} Gene, G303V, in Early-Onset Familial Progressive Supranuclear Palsy. Arch Neurol. 2005. 62(9):1444-1450.

Menendez J, Rodriguez-Navarro JA, Solano RM, Casarejos MJ, Rodal I, Guerrero R, Sanchez MP, Avila J, Mena MA, de Yebenes JG. Suppression of Parkin enhances nigrostriatal and motor neuron lesion in mice over-expressing human-mutated tau protein. Hum Mol Genet. 2006. 15(13):2045-58. (Epub 2006 May 12.)

Rodríguez-Navarro JM, Casarejos MJ, Menéndez J, Solano RM, Rodal I, Gómez A, de Yébenes JG, Mena MA. Mortality, oxidative stress and tau accumulation during aging in parkin null mice. J Neurochem. 2007, 103(1):98-114

Tai YF, Ahsan RL, de Yebenes JG, Pavese N, Brooks DJ, Piccini P. Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an (18)F-dopa PET study. J Neural Transm. 2007. 114(3):337-40. (Epub 2006 Aug 8).

Guerrero R, Navarro P, Gallego E, Avila J, de Yebenes JG, Sanchez MP. Park2-Null/Tau Transgenic Mice Reveal a Functional Relationship between Parkin and Tau. J Alzheimers Dis. 2008. 13(2):161-72

Rodriguez-Navarro JA, Casarejos MJ, Solano RM, Rodal I, Gomez A, Ampuero, I, Garcia de Yebenes J, Mena MA. Cerebral and systemic tau deposition, with multiple organomegaly, in mature parkin null, human mutated tau overexpressing mice. Human Mol Gen. (2008 in press)

Ros R, Ampuero I, García de Yébenes J.Parkin polymorphisms in progressive supranuclear palsy. J Neurol Sci. 2008. 268(1-2):176-8

Solano, RM; Casarejos, MJ.; Menéndez-Cuervo, J; Rodriguez-Navarro, JA.; García de Yébenes, J; Mena, MA.Glial dysfunction in parkin null mice. Effects of aging. J Neurosci. 2008, 28 (3):598-611.

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How has the grant you received influenced your future research?
The grant we received from The PSP Association was crucial in our search for the gene(s) responsible for PSP. The funding was mostly used to pay for patients travelling from Madrid to London for PET studies. That allowed us to detect presymptomatic subjects and to increase the power of the linkage analysis. Whilst looking for the gene responsible for PSP in the largest family we were fortunate to find, by serendipity, that in at least two other families the cause of PSP appeared to be related to two different proteins, parkin and tau, thereby opening up new avenues for research.

Dr Justo Garcia de Yebenes says,
"I would like to thank The PSP Association and all its supporters for their generosity and to thank the patients and their families for their unfailing enthusiasm and willingness to participate in these studies - without which none of this would be possible."