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Project

Molecular genetics and functional genomics of frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of irreversible clinical conditions that are characterized by progressive neuronal loss in the frontal and/or temporal cortices. Motor neuron disease (MND) and parkinsonism complicate the disease in up to 15% of patients, and overlap with symptoms of Alzheimer disease (AD), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP) is not uncommon. In the age group below 65 years, FTLD is the second most common type of neurodegenerative dementia after AD. There are currently no preventive or curative treatments available. To develop effective therapies our understanding of the pathological mechanisms leading to the neurodegenerative processes in the patients' brains is essential. Molecular genetic studies provide a gateway to uncover such mechanisms for further cell biological studies. FTLD has a strong genetic component: in up to 50% of patients, familial aggregation has been observed suggesting highly penetrant genetic factors. Mutations in four genes have been demonstrated to cause autosomal dominant forms of FTLD and common variants affecting expression of TMEM106B were suggested to confer genetic risk for FTLD. Further genetic heterogeneity does exist including a major disease locus at chromosome 9p. Using state-of-the-art molecular genetic and genomic strategies, we aim to further expand our understanding of the biochemical pathways that contribute to the etiology of FTLD. Familial FTLD patients that are not explained by mutations in the known genes will be studied to identify additional FTLD genes including the chromosome 9p gene. In addition we will identify novel risk and disease modifier genes in an extended population of FTLD patients. As a direct result of these molecular genetic studies, improved molecular diagnostics can be offered to the patients and their families, dramatically improving delay times towards correct diagnosis and treatment. Further, results obtained in this project will be the basis for subsequent cell biology studies of the functions and dysfunctions of pathways contributing to neurodegeneration in FTLD.
Date:1 Jan 2011 →  31 Dec 2012
Keywords:FUNCTIONAL GENOMICS, FRONTOTEMPORAL LOBAR DEGENERATION, MOLECULAR GENETICS
Disciplines:Genetics, Systems biology, Molecular and cell biology