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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Wise, Bradley C
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Washington University
Schools of Medicine
Saint Louis
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Avey, Denis; Sankararaman, Sumithra; Yim, Aldrin K Y et al. (2018) Single-Cell RNA-Seq Uncovers a Robust Transcriptional Response to Morphine by Glia. Cell Rep 24:3619-3629.e4
McGill, Bryan E; Barve, Ruteja A; Maloney, Susan E et al. (2018) Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of Ctcf in Camk2a-Cre-Expressing Neurons. J Neurosci 38:200-219
Sasaki, Yo; Hackett, Amber R; Kim, Sungsu et al. (2018) Dysregulation of NAD+ Metabolism Induces a Schwann Cell Dedifferentiation Program. J Neurosci 38:6546-6562
Kim, Sungsu; Maynard, Jason C; Strickland, Amy et al. (2018) Schwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUN. Proc Natl Acad Sci U S A 115:8019-8024
Essuman, Kow; Summers, Daniel W; Sasaki, Yo et al. (2018) TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes. Curr Biol 28:421-430.e4
Beirowski, Bogdan; Wong, Keit Men; Babetto, Elisabetta et al. (2017) mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells. Proc Natl Acad Sci U S A 114:E4261-E4270
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
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
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
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

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