Frontotemporal dementia (FTD) is a progressive neurodegenerative disease associated with focal atrophy of the prefrontal and/or temporal lobes. FTD is the second most common form of dementia among people under the age of 65. Many FTD-causing genes have been identified during the last decade, including CHMP2B, GRN, C9ORF72, and TBK1. Some of these genes are also implicated in the motor neuron disease amyotrophic lateral sclerosis (ALS), paving the way for in-depth mechanistic investigation of pathogenic processes in both disorders. In order to reveal common pathogenic mechanisms in different forms of FTD, it is critically important to investigate both common and rare genetic mutations. To this end, in this application, we will focus on the effects of FTD-causing mutations in CHMP2B and TBK1 on the functions of the endosomal- lysosomal and autophagy pathways, two closely linked cellular pathways for degradation of transmembrane and intracellular cargos. We will take advantage of strengths of different experimental systems including fruitfly Drosophila, mouse models of FTD and cortical neurons differentiated from CRISPR-engineered induced pluripotent stem cells (iPSCs). This multidisciplinary approach will greatly enhance our understanding of pathogenic mechanisms of FTD and reveal novel targets for therapeutic intervention.

Public Health Relevance

Program Narrative To understand pathogenic mechanisms of frontotemporal dementia and related disorders, we will use a combination of genetic, molecular and cellular approaches in mouse and Drosophila models as well as induced pluripotent stem cell models to perform a series of experiments. The proposed mechanistic studies will contribute to the development of therapeutic avenues for these insidious disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS057553-15
Application #
10059266
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Cheever, Thomas
Project Start
2018-01-01
Project End
2021-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
15
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Neurology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
West, Ryan J H; Ugbode, Chris; Gao, Fen-Biao et al. (2018) The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia. Hum Mol Genet 27:1382-1395
Yuva-Aydemir, Yeliz; Almeida, Sandra; Gao, Fen-Biao (2018) Insights into C9ORF72-Related ALS/FTD from Drosophila and iPSC Models. Trends Neurosci 41:457-469
Zhang, Zhijun; Almeida, Sandra; Lu, Yubing et al. (2013) Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS One 8:e76055
Jiao, Jian; Herl, Lauren D; Farese, Robert V et al. (2010) MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS One 5:e10551