Over the last 10 years, the lysosome-mediated degradation pathway macroautophagy has gained prominence in the field of adult onset neurodegeneration. Macroautophagy is an essential cellular pathway responsible for the elimination of cytosolic proteins, lipids and organelles. It is the most conserved of the three forms of autophagy, and its importance in mammals can be seen in a wide array of processes from the earliest stages of development to the maintenance of the aging brain. Although neurons were among the earliest cell types to be examined for macroautophagy, subsequent biochemical and genetic studies in liver and yeast caused the interest in neuronal macroautophagy to wane. Nonetheless, as the importance of macroautophagy in neurodegenerative diseases continues to grow, it is clear that we must refocus our attention on neural macroautophagy if we are truly to understand how this essential pathway impacts the adult brain. In this proposal, we will examine two key questions that will define how fundamental macroautophagic events are relevant in the healthy and diseased adult brain.
In Aim 1, we will define how membrane cholesterol impacts macroautophagy, and how disruptions in cholesterol homeostasis may lead to dysfunctional autophagy in the mammalian brain. Then in Aim 2, we will determine if aggregation-prone proteins are indeed eliminated by macroautophagy in the adult brain, and establish the minimal components essential for this process. By answering these questions, we will not only further our mechanistic understanding of key macroautophagic processes, but we will also understand them in a context that will further our understanding of how macroautophagy can impact neurodegenerative disease.

Public Health Relevance

To maintain a healthy neuron, disposal systems such as autophagy must be intact. In diseases of the aging brain, this pathway can play an important role to promote disease recovery. To identify how autophagy can help fight neurodegeneration, our proposal focuses on two key questions that will help determine therapeutic strategies to combat disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS063973-06A1
Application #
8887948
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (03))
Program Officer
Morris, Jill A
Project Start
2008-09-30
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
6
Fiscal Year
2015
Total Cost
$445,443
Indirect Cost
$99,149
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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