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Microfluidics-Assisted Selective Depolarization of Axonal Mitochondria
Published on: August 4, 2022
Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress
Craig Press1, Jeffrey Milbrandt
1Department of Pathology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Axonal degeneration is a prominent feature of many neurological disorders that are associated with mitochondrial dysfunction, including Parkinson's disease, motor neuron disease, and inherited peripheral neuropathies. Studies of the Wld(s) mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury, suggest that axonal degeneration is an active process. Wld(s) mice also have slower axonal degeneration and disease progression in numerous models of neurodegenerative disease. The Wld(s) mutation results in the production of a chimeric protein that contains the full-length coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which alone is sufficient for axonal protection in vitro. To test the effects of increased Nmnat expression on axonal degeneration induced by mitochondrial dysfunction, we examined dorsal root ganglion (DRG) neurons treated with rotenone. Rotenone induced profound axonal degeneration in DRG neurons; however, this degeneration was delayed by expression of Nmnat. Nmnat-mediated protection resulted in decreased axonal accumulation and sensitivity to reactive oxygen species (ROS) but did not affect the change in the rate of rotenone-induced loss in neuronal ATP. Nmnat also prevented axonal degeneration caused by exposure to exogenous oxidants and reduced the level of axonal ROS after treatment with vincristine, further supporting the idea that Nmnat promotes axonal protection by mitigating the effects of ROS.
Insights
Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat) protects axons from degeneration caused by mitochondrial dysfunction and oxidative stress. This finding offers a potential therapeutic target for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Axonal degeneration is a hallmark of neurodegenerative diseases linked to mitochondrial dysfunction.
- The Wld(s) mouse model demonstrates that axonal degeneration is an active, genetically influenced process.
- The Wld(s) mutation produces a protective chimeric protein containing nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1).
Purpose of the Study:
- To investigate the protective effects of increased Nmnat expression against mitochondrial dysfunction-induced axonal degeneration.
- To determine the mechanism by which Nmnat confers axonal protection.
Main Methods:
- Utilized dorsal root ganglion (DRG) neurons treated with rotenone to model mitochondrial dysfunction.
- Examined the impact of Nmnat expression on rotenone-induced axonal degeneration.
- Assessed reactive oxygen species (ROS) levels and ATP depletion in axons.
Main Results:
- Nmnat expression significantly delayed rotenone-induced axonal degeneration in DRG neurons.
- Nmnat-mediated protection reduced axonal accumulation and sensitivity to ROS.
- Nmnat did not alter the rate of ATP loss but mitigated ROS accumulation, suggesting a primary role in oxidative stress defense.
Conclusions:
- Nmnat confers significant axonal protection against mitochondrial dysfunction and oxidative stress.
- Nmnat's protective mechanism involves mitigating the detrimental effects of reactive oxygen species.
- Nmnat represents a promising therapeutic target for neurodegenerative conditions characterized by axonal degeneration.
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