Developmental and Activity-Dependent Expression of LanCL1 Confers Antioxidant Activity Required for Neuronal Survival

Abstract

SUMMARY Production of reactive oxygen species (ROS) increases with neuronal activity that accompanies synaptic development and function. Transcription-related factors and metabolic enzymes that are expressed in all tissues have been described to counteract neuronal ROS to prevent oxidative damage. Here, we describe the antioxidant gene LanCL1 that is prominently enriched in brain neurons. Its expression is developmentally regulated and induced by neuronal activity, neurotrophic factors implicated in neuronal plasticity and survival, and oxidative stress. Genetic deletion of LanCL1 causes enhanced accumulation of ROS in brain, and development-related lipid, protein, and DNA damage, mitochondrial dysfunction and apoptotic neurodegeneration. LanCL1 transgene protects neurons from ROS. LanCL1 protein purified from eukaryotic cells catalyzes the formation of thioether products similar to glutathione S-transferase. These studies reveal a neuron-specific glutathione defense mechanism that is essential for neuronal function and survival.

A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies

“…Mammalian brain also contains an unusual glutathione and LK-binding protein called LanCL1 (Chung et al, 2007; Hensley and Denton, 2015; Hensley et al, 2010a; Zhang et al, 2009) which is highly homologous to prokaryotic lanthionine synthase enzymes and which we have speculated might represent an alternative source of these compounds (Cooper, 2004; Chung et al, 2007; Hensley, 2010b; Hensley and Denton, 2015; Zhang et al, 2009). Interestingly, LanCL1 knock-out mice develop severe neuroinflammation and neurodegeneration beginning at 8 weeks of age but autophagy has yet to be assessed in these animals (Huang et al, 2014). LanCL1 is upregulated in some models of neurodegeneration including the SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS) (Chung et al, 2007); and natural variations in LanCL1 expression predict mouse strain sensitivity to the Parkinsonian neurotoxin, MPTP, with higher LanCL1 expression associated with resistance to the neurotoxin (Jones., 2013).…”

Alternative functions of the brain transsulfuration pathway represent an underappreciated aspect of brain redox biochemistry with significant potential for therapeutic engagement

“…To date, we have not been able to demonstrate an enzymatic function of either recombinant LanCL1 or the purified brain protein, though the methods we used may have damaged any inherent enzymatic potential. A very recent study by Huang et al reports a GST-like activity inherent to a LanCL1 that they engineered [69; discussed further, below].…”

“…More recently, Jones et al . colleagues identified LanCL1 as a major determinant in mouse strain variation in sensitivity to the Parkinsonian neurotoxin, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [75] and Huang et al report that LanCL1 knockout mice suffer severe neurodegeneration in the early adult period [69; discussed further, below].…”

Expanded Natural Product Diversity Revealed by Analysis of Lanthipeptide-Like Gene Clusters in Actinobacteria

“…However, LanC-like enzymes are widespread in eukaryotes, whereas the corresponding LanB homologs are not present (12,36). The molecular details of the functions of eukaryotic LanC-like enzymes remain largely elusive (56)(57)(58)(59)(60)(61). In prokaryotes, orphan LanCs have also been observed sporadically, which could possibly be evolutionary vestiges (12,21).…”