All neurodegenerative diseases (NDG) display mitochondrial dysfunction and this can lead to activation of AMP activated protein kinase (AMPK) either through a reduced cellular AMP/ATP ratio or via the production of reactive oxygen species. Active AMPK re-wires cellular metabolism by inhibiting catabolic and stimulating anabolic processes. While intuitively activated AMPK ought to be healthful for neurons, in several NDG models AMPK activation has been shown to be noxious to neurons. This proposal aims to identify the mechanism by which activated AMPK in neurons is injurious in cellular models of Amyotrophic Lateral Sclerosis (ALS). Neurons expressing mutant SOD or TDP43 (to model ALS) have enhanced glycolysis as a function of AMPK activation. Experiments in Specific Aim #1 test the hypothesis that by diverting glycolytic substrates away from the hexosamine biosynthetic and the pentose phosphate pathways - key pathways for maintaining healthy redox state and suppressing the unfolded protein response - activated AMPK is noxious to neurons. To translate these observations into a potential therapy for ALS patients we need to be able to manipulate glycolysis in neurons specifically - since inhibition of glycolysis in glial cells could have adverse effects.
In Specific Aim #2, we will use genetically modified mice to isolate ribosomes from neurons and glial cells separately and interrogate the associated mRNA for cell type specific variants of glycolytic enzymes. Rewiring metabolism in the setting of toxic proteins may be reporter for a subgroup of ALS patients that could respond to metabolism-targeted intervention.
In Specific Aim #3, we will determine the prevalence of metabolic re-wiring in fibroblasts re-programmed into neurons from ALS patients and controls. Understanding the neuron-specific adaptation to metabolic stress in NDG has the potential to uncover new targets for therapeutic intervention.

Public Health Relevance

Normal neurons and neurons experiencing neurodegenerative insults utilize fuel in distinct ways. This proposal investigates how metabolic adaptations in specific cells types influence survival of insulted neurons. Identifying the enzymes in neurons specifically that mediate these metabolic adaptations will lead to new therapeutic opportunities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS096746-01
Application #
9114785
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Gubitz, Amelie
Project Start
2016-03-15
Project End
2021-02-28
Budget Start
2016-03-15
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$492,894
Indirect Cost
$196,866
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104