The ALS-Related σ1R E102Q Mutant Eludes Ligand Control and Exhibits Anomalous Response to Calcium

Abstract

Sigma receptor type 1 (σ1R) is a transmembrane protein expressed throughout the central nervous system and in certain peripheral tissues. The human σ1R E102Q mutation causes juvenile amyotrophic lateral sclerosis (ALS), likely by inducing a series of alterations in calcium efflux from the endoplasmic reticulum (ER) to mitochondria that affects calcium homeostasis and cellular survival. Here, we report the influence of calcium on σ1R E102Q associations with glutamate N-methyl-D-aspartate receptors (NMDARs), binding immunoglobulin protein (BiP), and transient receptor potential calcium channels A1, V1, and M8. The mutant protein inhibited the binding of calmodulin to these calcium channels and interacted less with BiP than wild-type σ1R, thereby contributing to calcium homeostasis dysfunction. Mutant σ1R, but not wild-type σ1R, strongly bound to histidine triad nucleotide binding protein 1, which regulates neuromuscular synaptic organization and target selection through teneurin 1. While ligands regulated the association of σ1R wild-type with NMDARs and BiP, they failed to modulate the interaction between these proteins and the σ1R E102Q mutant. Thus, the σ1R E102Q mutant exhibited an anomalous response to cytosolic calcium levels, altered affinity for target proteins, and a loss of response to regulatory ligands. We believe that these modifications may contribute to the onset of juvenile ALS.

αN-Acetyl β-Endorphin Is an Endogenous Ligand of σ1Rs That Regulates Mu-Opioid Receptor Signaling by Exchanging G Proteins for σ2Rs in σ1R Oligomers

“…The σ1R C-terminal sequence contains two steroid binding-like domains (SBDL I and II) [63]. The human mutation E102Q located in the SBDL I (91-109) prevents classical ligands from regulating σ1R interactions with NR1 C1 NMDAR subunits and BiP [58], and our study indicates that α N-acetyl β-End 1-31 and β-End 1-31 have also lost their ability to regulate σ1R-σ2R and σ1R-NR1 C1 complexes.…”

“…However, α N-acetyl β-End 1-31 was weak at σ1R-BiP associations (Figure 7C). The σ1R human mutant E102R, which has been implicated in amyotrophic lateral sclerosis (ALS) [57], forms complexes with BiP and NR1 C1 proteins but eludes ligand control of these interactions [58]. Interestingly, this point mutation also prevented β-End 1-31 and σ N-acetyl β-End 1-31 from altering σ1R E102Q complexes with σ2R and NR1 C1 proteins (Figures S5 and S6).…”

Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?

“…Changes in mitochondria morphology are one of the first hallmarks observed in motor neurons of ALS patients [106] and in cell or animal TDP-43 or SOD1-related models of ALS [107][108][109], together with the reduction in cellular respiration and ATP production, due to deficits in complex I, II, III, and IV activity that have been found in different models, i.e., the postmortem spinal cord of sporadic ALS patients or from skeletal muscle and lymphocytes derived from them [110]. Increased levels of ROS and ROS-induced damage to DNA, RNA, proteins and lipids [111], and perturbations of calcium homeostasis have been observed in in vitro and in vivo ALS models harbouring mutations in SOD1, TDP-43, and FUS/TLS and in the motor nerve terminals of ALS patients [112][113][114][115][116][117][118]. Furthermore, a number of in vitro and in vivo experimental models have reported the impaired anterograde and retrograde transport of mitochondria, which leads to the aberrant clustering of mitochondria along the axon [119].…”

Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection

“…This complex dissociates in vitro within 60 min under ER stress simulation conditions or within 30 min if exposed to Sigma1R agonists [107]. The dissociation promotes activation of both chaperones [107,[129][130][131][132] and folding of target proteins [39,64]. Sigma1R p.E102Q (c.304G > C p.Glu102Gln rs387906829) mutation eliminates the ability of compounds with agonist properties to cause dissociation of the Sigma1R-BiP complex [107,132], indicating that Sigma1R chaperone activity depends on the protein-ligand interaction.…”