Defects in the endosomal-lysosomal pathway have been implicated in several neurodegenerative diseases but the detailed underlying molecular mechanisms remain largely unknown. Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes. FTLD is one of the most common forms of presenile dementia. Increasing clinical and molecular evidence indicates that FTLD and amyotrophic lateral sclerosis share many common pathogenic mechanisms. Indeed, several genes, including CHMP2B, VCP, TDP-43, FUS, Ubiquilin 2, and C9ORF72, have been implicated in the molecular pathogenesis of both diseases. During the first funding cycle of this R01 grant, we established a neuronal cell model and a Drosophila model of mutant CHMP2B toxicity and investigated the roles of ESCRTs and autophagy in neurodegeneration. To more closely model human disease, we established a novel transgenic mouse model that exhibits several key features of FTLD-associated neurodegeneration. In this renewal application, we propose to carry out molecular, cellular, genetic, and behavioral analyses to further characterize this novel mouse model of FTLD, with the goal of gaining mechanistic insights into pathogenic events in vivo. The proposed studies will significantly enhance our understanding of disease mechanisms in FTLD and may reveal novel targets for therapeutic interventions.

Public Health Relevance

In this proposal, we will perform a number of experiments to examine a novel mouse model of neurodegeneration. These studies will offer novel mechanistic insights into the neurotoxicity of mutant CHMP2B, which will likely enhance our understanding of molecular pathogenic mechanisms of frontotemporal dementia and amyotrophic lateral sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Gao, Fen-Biao; Almeida, Sandra; Lopez-Gonzalez, Rodrigo (2017) Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. EMBO J 36:2931-2950
Yin, Shanye; Lopez-Gonzalez, Rodrigo; Kunz, Ryan C et al. (2017) Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients. Cell Rep 19:2244-2256
Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva J et al. (2016) ALS-linked protein disulfide isomerase variants cause motor dysfunction. EMBO J 35:845-65
Biswas, Md Helal U; Almeida, Sandra; Lopez-Gonzalez, Rodrigo et al. (2016) MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations. Stem Cell Reports 7:316-324
Lopez-Gonzalez, Rodrigo; Lu, Yubing; Gendron, Tania F et al. (2016) Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons. Neuron 92:383-391
Almeida, Sandra; Gao, Fuying; Coppola, Giovanni et al. (2016) Suberoylanilide hydroxamic acid increases progranulin production in iPSC-derived cortical neurons of frontotemporal dementia patients. Neurobiol Aging 42:35-40
Peters, Owen M; Cabrera, Gabriela Toro; Tran, Helene et al. (2015) Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron 88:902-909
Yang, Dejun; Abdallah, Abbas; Li, Zhaodong et al. (2015) FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol 130:525-35
Freibaum, Brian D; Lu, Yubing; Lopez-Gonzalez, Rodrigo et al. (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:129-33
Tran, Helene; Almeida, Sandra; Moore, Jill et al. (2015) Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron 87:1207-1214

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