Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS)

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a "brake" on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed.

Keywords: ALS; C-terminals; Motoneurons; Sigma-1 receptor.

Fig. 1

Sigma-1 receptor reduces motoneuron excitability and slows ALS progression. A. Frequency-current relationships in motoneurons of SR1 KO (red) and WT (blue) mice. A significant increase in the slope of FeI relationship was apparent in S1R KO mice at current intensities > 700 pA (p < 0.05). Bars are ± standard errors. Number of recordings per intensity is shown above/below standard error bars. B. Kaplane-Meyer end stage curve. Median survival of mice is 186.0 days for ALS S1R WT mice (blue), and 127.0 days for ALS S1R KO mice (red). p < 0.0001; χ² = 32.29. Modified with copyright permission from: Mavlyutov et al., Neuroscience 2013; 240:129–34.

Fig. 2

The sigma-1 receptor (green signal in the left and middle panels) and the DMT producing enzyme INMT (green in the right panel) are localized to postsynaptic sites of C-terminals and juxtaposed to presynaptic cholinergic (ChAT positive) boutons (red). To demonstrate that the sigma-1 receptor is juxtaposed only to cholinergic postsynaptic densities of MNs we performed double labeling with antibodies against synaptophysin (a universal marker for different types of chemical synapses). Notice that not all synaptophysin-positive synapses are juxtaposed to the sigma-1 receptor. Blue (DAPI stain) indicates cell nuclei. Lower panel shows localization of sigma-1 receptor in subsurface cistern of cholinergic postsynaptic site. Modified with copyright permission from: Mavlyutov et al., Neuroscience 2012; 206: 60–80.

Fig. 3

Diagram showing our hypothesis for the role of the S1R in C-terminals: A. The S1R regulates the activity of potassium channels located in postsynaptic sites of C-terminals. In WT animals the S1R will activate potassium channels resulting in a larger afterhyperpolarization that reduces the firing frequency in motoneurons. In sigma-1 KO animals, a reduced afterhyperpolarization results in a higher firing frequency and a stronger muscle contraction. B and C: Two possible mechanisms showing how S1R can regulate the activity of potassium channels in the postsynaptic plasma membrane. B. The enzyme INMT produces the ligand that activates the S1R localized in the subsurface cisternae. Active S1R results in a conductance increase in calcium channels, and the subsequent opening of potassium channels (SK2 and/or Kv2.1) through calmodulin (CaM), leading to an after-hyperpolarization. C. S1R can directly interact with and modulate potassium channels, resulting in an increased conductance of the SK2 and/or Kv2.1 channels in the plasma membrane of C-terminals.