The PSP Association

Lead researchers Dr Alison M. Goate & Dt Pau Pastor
Co-researcher Dr Eduardo Tolosa

Institution Department of Psychiatry, Washington University, St. Louis, MO, USA

Duration 2 years
Start August 2003 End July 2005

Grant £47,000

Aim of research
• To identify 17q21 risk haplotypes in progressive supranuclear palsy (PSP) and cortical basal degeneration (CBD)
• To identify specific haplotypes associated with risk for PSP in at least two populations
• To identify the responsible gene for Hereditary Dysphasic Disinhibition Dementia 2.

About the research
The first step of the project was to determine if there are any rare variants in the 17q21 region forming a new pathogenic haplotype associated with PSP or CBD.
After analyzing several genetic markers in the Microtubule-Associated Protein Tau (MAPT) gene and surrounding genes in a PSP/CBD Spanish sample, we found specific haplotypes which were present only in patients with PSP. The haplotype was called H1E'A and was present in 16% of the patients and in 1% of the controls.

The next step was to test the frequency of the risk haplotype in other case-control samples in order to determine if a common risk haplotype, which would be linked to the risk for developing PSP, is shared between different populations.

We tested the frequency of the risk haplotype in an American sample of 200 patients with PSP, forty patients with CBD and in 240 North American controls provided by Dr. Dennis Dickson (US PSP Brain Bank, Jacksonville, Florida). The frequency of the H1E'A haplotype in the American neuropathological PSP series was significantly overrepresented in patients with pure PSP without any other neurodegenerative changes (12% in PSP cases versus 4% in healthy controls). We selected BACs covering the region of the MAPT gene and surrounding genes. Dr. Stavros Bastiardes from Dr. Michael Lovett's group (Department of Genetics, Washington University, St. Louis, MO) performed the hybridation of the BACs.

After typing new individuals of the HDDD2 family, we detected that the haplotype disease was also present in healthy individuals showing incomplete penetrance. To identify the mutation linked to HDDD2 we performed a genome wide scan with the analysis of 400 microsatellites in the kindred in order to detect different loci involved on HDDD2. We found only significant linkage at chromosome 17q21. We sequenced several candidate genes and found genetic variants that were considered polymorphisms.

Findings
In this work we identified a haplotype on chromosme 17 that is present mostly in patients with PSP. This haplotype could contain the pathogenic variant linked to PSP (Pastor et al., 2004). Following on from this work we are now analyzing the frequency of the H1E'A haplotype in a larger sample. We have identified a genetic region that looks promising and are recruiting new cases and controls in Europe in order to reach this goal.

We are conscious that the direct selection method has its limitations and will therefore repeat several hybridizing experiments in order to cover the entire region of the MAPT gene.

In 2005, we identified the genetic cause of a family with frontotemporal dementia in a neighbouring gene of TAU, called progranulin (Mukherjee, 2005).

What does the outcome of this research mean for people with PSP?
The cause of PSP is unknown. However, we have strong evidence of a genetic factor located in a region of chromosome 17. Thanks to the support of The PSP Association, several research teams including our own are narrowing the candidate region and hopefully we will soon have a better understanding of the genetic factors involved in PSP.

Publications arising from the work
Johnson J, Ostojic J, Lannfelt L, Glaser A, Basun H, Rogaeva E, Kawarai T, Bruni A, St George Hyslop PH, Goate A, Pastor P, Chakraverty S, Norton J, Morris JC, Hardy J, Singleton A. No evidence for tau duplications in frontal temporal dementia families showing genetic linkage to the tau locus in which tau mutations have not been found. Neurosci Lett. 2004 Jun 10;363(2):99-101.

Pastor P, Ezquerra M, Perez JC, Chakraverty S, Norton J, Racette BA, McKeel D, Perlmutter JS, Tolosa E, Goate AM. Novel haplotypes in 17q21 are associated with progressive supranuclear palsy. Ann Neurol. 2004 Aug;56(2):249-58.

Zarranz JJ, Ferrer I, Lezcano E, Forcadas MI, Eizaguirre B, Atares B, Puig B, Gomez-Esteban JC, Fernandez-Maiztegui C, Rouco I, Perez-Concha T, Fernandez M, Rodriguez O, Rodriguez-Martinez AB, de Pancorbo MM, Pastor P, Perez-Tur J. A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease. Neurology. 2005;10;64(9):1578-85.

Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz Grinberg L, Liscic RM, Armendariz J, Morris JC, Goate AM.: HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol. 2006 Sep;60(3):314-22.

National/international presentations given on this work
MI Behrens, JB Norton, CM Roe S Chakraverty, P Pastor, AM Goate, DW McKeel, JC Morris. Comparison of Clinical Phenotype of Two Families with Hereditary Dysphasic Disinhibition Dementia (HDDD1 and HDDD2). 56th Annual Meeting of the American Academy of Neurology, May, 2003.

P. Pastor, M. Ezquerra, J. C. Perez, S. Chakrataverty, J. Norton, E. Tolosa, B. A. Racette, A.M. Goate. Haplotype structure of the 17q21 region in progressive supranuclear palsy and corticobasal degeneration. 9th International Conference on Alzheimer's Disease and Related Disorders. Philadelphia , July 2004.

Cairns NJ, Tu P Pastor P, et al. Hereditary Dysphasic Disinhibition Demenyia is a Chromosome 17q21-linkad frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions. Alzheimer's Association 10th International Conference on Alzheimer's Disease and Related Disorders. July 15-20, 2006, Madrid, Spain.

Pastor P. Novel and risk haplotypes spanning the MAPT locus are strongly associated with Progressive Supranuclear Palsy. The 2004 Society for Progressive Supranuclear Palsy International PSP Research Symposium. October 28, 2004. San Diego, CA.

Pastor P. Genetic analysis of the 17q21 region in sporadic tauopathies. The 2005 Society for Progressive Supranuclear Palsy International PSP Research Symposium. Funded by the Peebler PSP Research Foundation. November 17, 2005. Arlington, Virginia. Estados Unidos.

Pastor P. ‘Update on genetic causes of frontotemporal dementia and related neurodegenerative tauopathies'. Meeting of the International Psychogeriatric Association, Symposium on ‘Physiopathology of Dementia'. Lisbon, Portugal, May 4,2006.

How has the grant you received influenced your future career and research direction?

Dr Pau Pastor says,
"Since July 2005 my work on PSP genetics has been supported with funding from the Government of Navarre (Spain). I am currently setting up a research group in Spain and we are going to focus our work on identifying the genetic variants responsible for PSP.

I am grateful to The PSP Association for awarding me this grant and especially want to thank all its supporters, patients and their families for their generosity in raising and donating funds, without which this research would not have been possible."