Abnormal neuronal activity, injury, and aging exert physical stress on the nervous system, leading to neuronal dysfunction and degeneration. NMNATs (nicotinamide mononucleotide adenylyl transferases) play a central role in maintaining neuronal integrity following a wide range of environmental challenges. Neuroprotection by NMNAT overexpression appears to be widespread as its overexpression delays axonopathy following nerve injury and ameliorates neurodegeneration in several neurodegenerative models, including Charcot-Marie- Tooth disease and tauopathies. The broad protective effects of NMNAT suggest that it protects at a step common to numerous neurodegenerative processes and raises the possibility that manipulating NMNAT expression or activity may provide a unique opportunity to develop therapies for treating many neurodegenerative diseases. There are three mammalian NMNAT homologs, NMNAT1-3, with NMNAT2 being the most labile isoform. Impairing NMNAT2 function leads to axonal degeneration in the peripheral nervous system. Our preliminary studies revealed that NMNAT2 levels in Alzheimer Disease (AD) patient cerebral cortex are reduced by more than 60%. Using the FTDP-17 tauopathy animal model, rTg4510 mice, we found that NMNAT2 levels were substantially decreased prior to the onset of neurodegeneration. Most importantly, exogenous Nmnat2 expression in rTg4510 hippocampus reduced neurodegeneration and the accumulation of toxic tau species. We hypothesize that NMNAT2 is required to maintain neural function and to reduce toxic protein accumulation in many different contexts. The goal of this proposal is to use cultured mouse and human cells as well as transgenic mouse models to elucidate the mechanisms underlying NMNAT2 protection against neurodegeneration and maintaining the health of mature neurons.

Public Health Relevance

More than six million Americans suffer from neurodegenerative diseases. We are studying how a protein called NMNAT2 provides neuroprotection in the mammalian central nervous system with a long-term goal of developing therapies to treat neurodegenerative diseases, including Alzheimer's Disease and tauopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS086794-06S1
Application #
9830970
Study Section
Program Officer
Mcgavern, Linda
Project Start
2019-05-15
Project End
2020-05-31
Budget Start
2019-05-15
Budget End
2020-05-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Sharma, Salil; Khadimallah, Ines; Corya, Adam Williamson et al. (2018) Presymptomatic change in microRNAs modulates Tau pathology. Sci Rep 8:9251
Sharma, Salil; Lu, Hui-Chen (2018) microRNAs in Neurodegeneration: Current Findings and Potential Impacts. J Alzheimers Dis Parkinsonism 8:
Huang, Jui-Yen; Lu, Hui-Chen (2018) mGluR5 Tunes NGF/TrkA Signaling to Orient Spiny Stellate Neuron Dendrites Toward Thalamocortical Axons During Whisker-Barrel Map Formation. Cereb Cortex 28:1991-2006
Huang, Jui-Yen; Lynn Miskus, Marisha; Lu, Hui-Chen (2017) FGF-FGFR Mediates the Activity-Dependent Dendritogenesis of Layer IV Neurons during Barrel Formation. J Neurosci 37:12094-12105
Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen (2017) Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Sci Rep 7:43846
Itami, Chiaki; Huang, Jui-Yen; Yamasaki, Miwako et al. (2016) Developmental Switch in Spike Timing-Dependent Plasticity and Cannabinoid-Dependent Reorganization of the Thalamocortical Projection in the Barrel Cortex. J Neurosci 36:7039-54
Ballester-Rosado, Carlos J; Sun, Hao; Huang, Jui-Yen et al. (2016) mGluR5 Exerts Cell-Autonomous Influences on the Functional and Anatomical Development of Layer IV Cortical Neurons in the Mouse Primary Somatosensory Cortex. J Neurosci 36:8802-14
Lu, Hui-Chen; Mackie, Ken (2016) An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry 79:516-25
Ali, Yousuf O; Allen, Hunter M; Yu, Lei et al. (2016) NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies. PLoS Biol 14:e1002472
Slivicki, Richard A; Ali, Yousuf O; Lu, Hui-Chen et al. (2016) Impact of Genetic Reduction of NMNAT2 on Chemotherapy-Induced Losses in Cell Viability In Vitro and Peripheral Neuropathy In Vivo. PLoS One 11:e0147620

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