The development of new treatments for neurodegenerative diseases is a major unmet medical need, with the numbers of affected individuals (already tens of millions worldwide) projected to dramatically increase with the aging population. Axonal dysfunction appears to be an early event in many of these disorders, thus it has become a prime focus for the development of new treatments for these conditions. AxD is a self-destructive process that is similar to, but distinct from, apoptosis. Most studies indicate that it is a caspase-independent process as manipulation of the mitochondrial apoptotic machinery or caspase inhibitors fail to block AxD. However, the recent identification of an APP/DR6/Casp6 axon degeneration pathway induced by trophic factor deprivation suggests a link between these two processes. Studies of the wlds mutant mouse led to the discovery that the NAD biosynthetic enzyme Nmnat1 can protect axons from a wide variety of insults, including mechanical trauma, loss of trophic support, and mitochondrial inhibition. Nmnat enzymatic activity is required for the axonal protective effects;however, its mechanism of action remains obscure. In this proposal, we outline experiments aimed at 1) identifying the signaling pathway(s) responsible for axonal surface APP (sAPP) shedding, caspase 6 (Casp6) cleavage, and axonal degeneration (AxD) induced by trophic factor deprivation using Ret knockin Tyr->Phe mutant mice;2) understanding the mechanism by which Nmnat protects axons after trophic factor deprivation without altering cleaved Casp6 levels via monitoring cleavage of Casp6 targets;3) investigating the idea that different Nmnat isoforms produce NAD for specific neuronal subcellular compartments important for axonal integrity or that they have additional functions besides NAD production, such as the synthesis of novel metabolites that are important mediators of axonal protection;and 4) testing the therapeutic efficacy of combined neurotrophic factor and axonal protectant treatment in animal models of Parkinson's disease. If the proposed combination therapy shows dramatically increased benefit over single agent therapy in the PD models, this could have a wide-ranging impact as it is likely to be applicable to other neurodegenerative diseases. Overall, we believe that understanding the convergence of growth factor signaling and the common Nmnat-sensitive pathway of axon self-destruction could foster new therapeutic strategies for a wide range of disease and injury conditions.

Public Health Relevance

The breakdown of the connections between neurons is a common occurrence in Parkinson's disease and Alzheimer's disease. Neurons lacking their connections cannot communicate and eventually die. The development of drugs to block the loss of these neuron connections is a promising avenue for finding better treatments for neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013730-19
Application #
8701205
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wise, Bradley C
Project Start
1996-08-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Summers, Daniel W; Gibson, Daniel A; DiAntonio, Aaron et al. (2016) SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A 113:E6271-E6280
Sasaki, Yo; Nakagawa, Takashi; Mao, Xianrong et al. (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD(+) depletion. Elife 5:
Gerdts, Josiah; Summers, Daniel W; Milbrandt, Jeffrey et al. (2016) Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 89:449-60
Kim, Sungsu; Maynard, Jason C; Sasaki, Yo et al. (2016) Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity. J Neurosci 36:9633-46
Musiek, Erik S; Xiong, David D; Patel, Tirth et al. (2016) Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy. Ann Clin Transl Neurol 3:434-42
Goyal, Manu S; Venkatesh, Siddarth; Milbrandt, Jeffrey et al. (2015) Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development. Proc Natl Acad Sci U S A 112:14105-12
Sasaki, Yo; Margolin, Zachary; Borgo, Benjamin et al. (2015) Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. J Biol Chem 290:17228-38
Gerdts, Josiah; Brace, E J; Sasaki, Yo et al. (2015) SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science 348:453-7
Summers, Daniel W; DiAntonio, Aaron; Milbrandt, Jeffrey (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J Neurosci 34:9338-50
Beirowski, Bogdan; Babetto, Elisabetta; Golden, Judith P et al. (2014) Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Nat Neurosci 17:1351-61

Showing the most recent 10 out of 87 publications