Frontotemporal dementia (FTD) is a neurodegenerative disease that accounts for 10-20% of dementia casesunder the age of 65 and is typically fatal within the five years of diagnosis. There are currently no effectivetherapeutics. Single nucleotide polymorphisms (SNPs) in the gene TMEM106B were recently found to be a riskfactor in FTLD-TDP, a major neuropathological subset of FTD. The TMEM106B risk genotype is alsoassociated with higher TMEM106B levels, lower plasma progranulin levels, and earlier onset of disease inpatients carrying mutations in the progranulin gene. This effect on progranulin is notable, as ~10% of FTLD-TDP is caused by mutations in this neurotrophic growth factor. These disease-associated mutations result ineither decreased expression or decreased secretion of progranulin, and thus insufficient progranulin seems tobe a major driver of disease. Given the effects of TMEM106B on progranulin, early efforts have been made tolearn more TMEM106B, a minimally characterized protein. Preliminary evidence has shown that increasedexpression of TMEM106B alters the endolysosomal equilibrium of cells as well as the distribution ofprogranulin, increasing its intracellular levels. The major premise of this proposal is that increased levelsof TMEM106B, as associated with the FTLD-TDP risk haplotype, 1) alter and impair endo-lysosomalpathways and functions and 2) that this endolysosomal perturbation impairs progranulin trafficking,resulting in the loss of its neurotrophic effects. In line with this premise, several aims are pursued: 1) Todetermine the function of TMEM106B in the endolysosomal pathway and elucidate the mechanism by whichincreased TMEM106B results in endolysosomal disequilibrium 2) To determine the mechanism ofTMEM106B's effect on progranulin levels and assess if altered TMEM106B levels affect progranulin'sneurotrophic effects. In pursuit of these aims, immunohistochemistry, biochemistry, subcellular fractionation,and survival experiments will be conducted in immortalized cell lines as well as in primary mouse neurons.Elucidation of the normal function of TMEM106B and its dysfunction in disease could yield importanttherapeutic targets that would focus on restoring progranulin's neurotrophic effects.

Public Health Relevance

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease that accounts for ~10-20% of dementia cases in patients under the age of 65 and there are currently no effective treatments. Genetic variants in TMEM106B; a minimally characterized gene; were found to significantly associate with disease. Therefore; we propose to determine the function of TMEM106B and its role in the development of disease to help identify novel potential therapeutic targets.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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NST-2 Subcommittee (NST)
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Sutherland, Margaret L
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University of Pennsylvania
Schools of Medicine
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Busch, Johanna I; Unger, Travis L; Jain, Nimansha et al. (2016) Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet 25:2681-2697