During neurodevelopment, more neurons are initially generated than are necessary. To prune away these superfluous neurons, neuronal death is required. While loss of neurons is necessary during development, neuronal death in the adult nervous system is highly detrimental, as these neurons must persist for the lifetime of the organism. As such, there need to exist tightly-regulated mechanisms that preserve neuronal viability. The identity of these pathways and whether they are perturbed in neurodegenerative disease remain poorly understood. The six-transmembrane protein GDE2 has been previously identified as a cell surface GPI-anchor cleaving enzyme that regulates Notch signaling during neurogenesis through the cleavage of GPI-anchored proteins. Recent evidence shows that levels of GDE2 and its GPI anchor-cleaving activity persist in the adult nervous system and that loss of GDE2 (Gde2-/-) results in slow, progressive neurodegeneration in mice. The proposed studies aim to define the neuropathology of Gde2-/- mice through immunohistochemical and biochemical analyses, to identify the downstream GPI-anchored proteins that mediate the neuroprotective function of GDE2, and to determine relevance for GDE2 dysfunction in human neurodegenerative diseases. Preliminary evidence identifies a target for GDE2 that mediates neuronal survival and demonstrates its altered processing in Alzheimer's disease patients. Taken together, these data suggest that GDE2 may regulate an important neuroprotective pathway that is perturbed in Alzheimer's disease. As the aging population grows, so too will the need for solutions to aging-associated diseases. With 5.3 million people afflicted with Alzheimer's disease in the U.S. alone and the annual rate of disease-related deaths increasing every year, finding an effective treatment for Alzheimer's disease is crucial. Currently, Alzheimer's disease is being treated palliatively, and recent clinical trials have generally been ineffective, with most targeting behavioral symptoms or terminal pathologic features. Accordingly, there is a dire need for mechanism-based therapies and biomarkers that detect early signs of decline in patients. The proposed studies may uncover the potential for GDE2 and its GPI-anchored substrates as exciting and promising avenues for research in the quest for next generation Alzheimer's disease therapeutic targets and fluid biomarkers.

Public Health Relevance

Neuronal survival is vital for the health of the adult nervous system, but the exact mechanisms governing neuroprotection, and whether such mechanisms are involved in the etiology of neurodegenerative diseases, remain unknown. The proposed studies will elucidate a novel protein cleavage mechanism underlying neuronal survival and determine if such a pathway is perturbed in neurodegenerative diseases such as Alzheimer's disease. Understanding basic pathways that mediate neuroprotection and how the process goes awry in disease can help in the much-needed identification of novel, mechanism-based pharmacological targets and diagnostic biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG056088-02
Application #
9525579
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
2017-07-03
Project End
2019-07-02
Budget Start
2018-07-03
Budget End
2019-07-02
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205