Abstract
Genetic mutations in nitrogen permease regulator-like 2 (NPRL2) are associated with a wide spectrum of familial focal epilepsies, autism, and sudden unexpected death of epileptics (SUDEP), but the mechanisms by which NPRL2 contributes to these effects are not well known. NPRL2 is a requisite subunit of the GAP activity toward Rags 1 (GATOR1) complex, which functions as a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) kinase when intracellular amino acids are low. Here, we show that loss of NPRL2 expression in mouse excitatory glutamatergic neurons causes seizures before death, consistent with SUDEP in humans with epilepsy. Additionally, the absence of NPRL2 expression increases mTORC1-dependent signal transduction and significantly alters amino acid homeostasis in the brain. Loss of NPRL2 reduces dendritic branching and increases the strength of electrically stimulated action potentials (APs) in neurons. The increased AP strength is consistent with elevated expression of epilepsy-linked, voltage-gated sodium channels in the NPRL2-deficient brain. Targeted deletion of NPRL2 in primary neurons increases the expression of sodium channel Scn1A, whereas treatment with the pharmacological mTORC1 inhibitor called rapamycin prevents Scn1A upregulation. These studies demonstrate a novel role of NPRL2 and mTORC1 signaling in the regulation of sodium channels, which can contribute to seizures and early lethality.
Highlights
Nitrogen permease regulator-like 2 (NPRL2) is a requisite subunit of Gap Activity TOward Rags 1 (GATOR1), an evolutionarily conserved complex that is comprised of three proteins called NPRL2, NPRL3, and DEPDC5 (DEP Domain Containing 5)
GATOR1 functions as a negative regulator of mammalian Target Of Rapamycin Complex 1 (mTORC1), a dynamic protein kinase that controls cellular growth, protein translation, and metabolic processes in cells (Bar-Peled et al, 2013; Liu and Sabatini, 2020). mTORC1 activity is controlled by distinct upstream regulatory protein complexes comprised of GATOR1 and TSC1/2, which function as GTPase activating proteins toward small GTP-binding proteins on the lysosomal surface called RAGs and Rheb, respectively (Efeyan et al, 2013; Meikle et al, 2007; Sancak et al, 2010)
Human mutations in NPRL2 are associated with a spectrum of neurological disorders, including autism, epilepsy, and sudden unexpected death of epileptics (SUDEP)
Summary
Nitrogen permease regulator-like 2 (NPRL2) is a requisite subunit of Gap Activity TOward Rags 1(GATOR1), an evolutionarily conserved complex that is comprised of three proteins called NPRL2, NPRL3, and DEPDC5 (DEP Domain Containing 5). Individuals with GATOR1 mutations can present with focal cortical dysplasia, with defects in cortical lamination and the presence of dysmorphic neurons (Cen et al, 2017; Kabat and Król, 2012; Scerri et al, 2015; Weckhuysen et al, 2016). These malformations have been found to occur through a two-hit genetic mechanism (Ribierre et al, 2018), confounding the specific. MTORC1 activity is controlled by distinct upstream regulatory protein complexes comprised of GATOR1 and TSC1/2, which function as GTPase activating proteins toward small GTP-binding proteins on the lysosomal surface called RAGs and Rheb, respectively (Efeyan et al, 2013; Meikle et al, 2007; Sancak et al, 2010).
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