Investigating physiological pathways modulating TAU homeostasis: potential implications for alzheimer's disease and related dementia
Ended Project Grant Awarded Last action
- Award ID
- F31AG087599
- Recipient
-
The Johns Hopkins University UEI FTMTDMBR29C7
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $143,669
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Place of performance
- Maryland, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cytoskeletal abnormalities are prominent features in a wide variety of neurodegenerative diseases and have been attributed to induce neuronal death. In alzheimer's disease (ad) and ad-related dementias such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD), microtubule-associated protein TAU (TAU) is hyperphosphorylated and aggregates into neurofibrillary tangles (nfts), which contributes to mitochondrial dysfunction, disrupted autophagy, and neuronal death. Despite the critical role of TAU abnormalities in neurodegenerative diseases like ad and ALS-FTD, how this dysregulation arises is not fully understood. Our group has found a signaling pathway that when disrupted, leads to changes in TAU post-translational modifications that are associated with disease. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is the only known protein in vertebrates that acts at the cell surface in neurons to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers a subclass of proteins to the membrane. GDE2 has been shown to aberrantly accumulate intracellularly in neurons of patients with ad and ALS. Consistent with GDE2 dysfunction in disease, biochemical studies in postmortem ad brain confirm impaired GPI-anchored protein processing, while proteomic studies of patient cerebrospinal fluid (CSF) reflect a decrease in neuronally expressed GPI-anchored proteins in the CSF of ALS patients. GDE2 deletion in the APP/PS1 mouse model of amyloidosis leads to an increase in TAU phosphorylation, and preliminary studies in primary cultured neurons from the PS19 humanized tauopathy mouse model show that loss of GDE2 results in increased TAU levels and phosphorylation. These observations suggest that GDE2 is required for regulating the dynamics of TAU phosphorylation. The overarching hypothesis to be tested in this proposal is that GDE2 is an important regulator of TAU post-translational modifications and that GDE2 inactivation contributes to TAU abnormalities in disease. In aim 1, i will utilize the PS19 model to examine how the loss of GDE2 affects the onset and progression of neurodegeneration in the context of TAU modifications and aggregation in vivo and in vitro. In aim 2, i will explore the pathway through which GDE2 modulates TAU post-translational modifications through structure-function analysis of GDE2 and by taking a candidate-based approach that focuses on select GPI-anchored substrates associated with ad and adrds. In aim 3, i will determine the relevance of GDE2 to TAU pathology in ad postmortem brain. Together, the outcomes of my project will provide insight into pathways relevant to TAU pathology observed in ad and adrds and could provide novel targets for therapeutic intervention.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$3,253 | |
| Amendment | $0 | |
| Amendment | $48,974 | |
| Amendment | $48,974 | |
| Amendment | $0 | |
| Amendment | $48,974 | |
| Original award | $0 |
Quick answers
Who received award F31AG087599?
F31AG087599 was awarded to The Johns Hopkins University by National Institute on Aging (National Institutes of Health) on November 20, 2024.
How much is award F31AG087599 worth?
$143,669 has been obligated on F31AG087599.
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