Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive neurodegenerative disease characterized by the selective loss of both upper and lower motor neurons (MNs) [1]
We found that central nervous system (CNS)-specific Lanthionine synthetase C-like protein 1 (LanCL1) transgene delays disease onset, decelerates disease progression, and prolongs lifespan in the SOD1G93A mouse model of ALS
These disease-modifying effects of LanCL1 transgene might be a direct result of its role in protecting the MNs in the spinal cord from degeneration in the ALS model, as the agedependent loss of spinal MNs is significantly delayed
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive neurodegenerative disease characterized by the selective loss of both upper and lower motor neurons (MNs) [1]. Loss of these neurons causes muscle weakness, spasticity, atrophy, paralysis, and premature death [2]. Transgenic rodents carrying mutant forms of SOD1 develop a similar, progressive MN disease akin to patients [4]. ALS is more frequent in males [5], and the male patients tend to have an earlier age of onset, but the cause for this gender bias remains enigmatic [6]. How to promote neuron survival remains an unmet need in ALS treatment
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