Neurodegenerative diseases have become enormous financial and societal burdens as human life expectancy has increased. Misregulation of autophagy has been implicated in neurodegenerative disorders, including Alzheimer?s Disease, Parkinson?s Disease and Huntington?s Disease. While many studies have elucidated autophagy and its role in cellular homeostasis in yeast and mammalian cell culture, much less in known about autophagy in neurons. Autophagosome biogenesis is known to occur at the distal tips of axons, and recent studies have indicated that presynaptic activity modulates autophagosome biogenesis. Our preliminary data suggests that autophagosome biogenesis and flux decrease with age in neurons. Our preliminary data further suggest that the kinetics of autophagosome assembly factors are disrupted in aged neurons compared to young neurons. We propose to uncover the temporal dynamics of autophagosome biogenesis, cargo uptake, maturation, trafficking, and acidification in neurons during aging. We will examine these changes in young and aged mice and compare wild type mice to mouse models of neurodegenerative diseases. Our studies will help us elucidate how aging modulates autophagy, which will further our understanding of how misregulation of autophagy leads to serious neurodegenerative diseases. Similarly, uncovering how autophagosome biogenesis is regulated during aging will be important for developing treatments for autophagy-related neurodegenerative diseases.

Public Health Relevance

Neurodegenerative diseases have become enormous financial and societal burdens as human life expectancy has increased. Misregulation of autophagy has been implicated in neurodegenerative disorders, such as Alzheimer?s Disease, Huntington?s Disease and Parkinson?s Disease. To understand how misregulation of autophagy contributes to neurodegenerative disease, our proposal will elucidate how autophagy dynamics change in neurons over time, with a particular focus on how autophagy is spatially and temporally modulated during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS100348-01
Application #
9256320
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sutherland, Margaret L
Project Start
2016-12-01
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Stavoe, Andrea K H; Holzbaur, Erika L F (2018) Axonal autophagy: Mini-review for autophagy in the CNS. Neurosci Lett :