Mutations in the progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD). Individuals with GRN mutations have a 50% reduction in functional progranulin protein (PGRN) and also invariably display TDP-43 pathology (FTLD-TDP), indicating low PGRN levels as a potential initiator of TDP-43 dysfunction in FTLD. The identification of TDP-43 as the pathological protein, not only in patients with FTLD with mutations in GRN, but also in the majority of patients with ALS further suggests a role for TDP-43 in a unifying neurodegenerative disease mechanism underlying these disorders. Consequently, determining how PGRN levels are regulated in brain may lead to novel treatments and therapies for a range of neurodegenerative diseases. In the last few years, we and others have identified two PGRN regulators through genome-wide association studies: the uncharacterized transmembrane protein 106B (TMEM106B) and the multiligand receptor sortilin (SORT1). TMEM106B was identified as a risk factor for FTLD-TDP, with subsequent studies from our laboratory suggesting a role for TMEM106B in PGRN regulation. Of particular interest was the finding that a specific TMEM106B genetic variant (rs3173615 predicted to result in p.T185S) could significantly protect GRN mutation carriers from developing disease. We further identified SORT1 as a major regulator of PGRN levels in human plasma. Interestingly, SORT1 was independently identified as a neuronal receptor for PGRN. In preliminary data we now present an unpublished genome-wide quantitative trait locus analysis of GRN mRNA levels in human brain and identify TBC1 domain family, member 1 (TBC1D1) as yet another novel PGRN regulator. In this Project, we hypothesize that genetic variants in TMEM106B, SORT1 and TBC1D1 regulate PGRN levels and/or function in brain, thereby modifying disease risk, penetrance and presentation in TDP-43 proteinopathies.
The Specific Aims are focused on 1) the functional characterization of the effect of the p.T185S protective variant on TMEM106B and PGRN using cell culture models, including primary cultures of mouse Pgrn knock-out and wild type hippocampal neurons, biochemical and molecular approaches and """"""""somatic gene transfer"""""""" in mice using recombinant adeno-associated virus;2) Systematic analyses of the role of genetic variants in TMEM106B, SORT1 and TBC1D1 in the development and presentation of FTLD and ALS by performing genetic association studies in extensive FTLD and ALS case- control populations using variants identified by whole-genome sequencing;and 3) determine the effect of newly identified TMEM106B, SORT1 and TBC1D1 variants on PGRN levels in vivo and in vitro. The proposed studies are relevant to fully appreciate the contribution of common and rare variants in TMEM106B, SORT1 and TBC1D1 to the development and presentation of FTLD and ALS and will lead to a greater understanding of PGRN regulation.
This proposal is designed to identify and functionally characterize genetic variants in TMEM106B, SORT1 and TBC1D1 that play a role in the development and presentation of FTLD and ALS. The identification of factors that may increase the amount of PGRN available to cells is important and could lead to disease-modifying therapies for FTLD and related TDP-43 proteinopathies.
|Koga, Shunsuke; Josephs, Keith A; Ogaki, Kotaro et al. (2016) Cerebellar ataxia in progressive supranuclear palsy: An autopsy study of PSP-C. Mov Disord 31:653-62|
|Rodriguez-Porcel, Federico; Lowder, Lindsey; Rademakers, Rosa et al. (2016) Fulminant corticobasal degeneration: Agrypnia excitata in corticobasal syndrome. Neurology 86:1164-6|
|Heckman, Michael G; Soto-Ortolaza, Alexandra I; Sanchez Contreras, Monica Y et al. (2016) LRRK2 variation and dementia with Lewy bodies. Parkinsonism Relat Disord 31:98-103|
|Nicholson, Alexandra M; Rademakers, Rosa (2016) What we know about TMEM106B in neurodegeneration. Acta Neuropathol 132:639-651|
|Williams, Kelly L; Topp, Simon; Yang, Shu et al. (2016) CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun 7:11253|
|Nicholson, Alexandra M; Finch, NiCole A; Almeida, Marcio et al. (2016) Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun 7:11992|
|van Blitterswijk, Marka; Rademakers, Rosa (2015) Neurodegenerative disease: C9orf72 repeats compromise nucleocytoplasmic transport. Nat Rev Neurol 11:670-2|
|Kertesz, A; Finger, E; Murrell, J et al. (2015) Progressive supranuclear palsy in a family with TDP-43 pathology. Neurocase 21:178-84|
|Pottier, Cyril; Bieniek, Kevin F; Finch, NiCole et al. (2015) Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 130:77-92|
|Aoki, Naoya; Murray, Melissa E; Ogaki, Kotaro et al. (2015) Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A. Acta Neuropathol 129:53-64|
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