Table 3.
Non-seizure DEE-like phenotypes associated with Sigma1R genetic deficiency models or genetic linkage analyses in other disorders.
| Phenotype | Model | Molecular Mechanism | Reference |
|---|---|---|---|
| Inflammatory stress | Sigma1R knockout mice | Hypercytokinemia was induced by acute inflammation with restricted endonuclease activity of IRE1, an ER stress sensor | Rosen 2019 [64] |
| Memory | Sigma1R knockout in APPSwe Alzheimer’s disease mouse model | Memory impairment was exacerbated with increased oxidative stress in the hippocampus | Ryskamp 2019 [69] |
| Phase 2a clinical trials (phase 2b/3 ongoing) | ANAVEX 2-73 (blarcamesine), a Sigma1R agonist with some muscarinic modulatory activity, reduced cognitive decline in a longitudinal 148-week study of patients with Alzheimer’s disease | Hampel 2019 [57]; NCT03790709 | |
| Fmr1-KO2 mouse model of fragile X-autism-related disorders model | ANAVEX 2-73 (blarcamesine) reversed Fmr1-KO2 deficit in learning and memory as measured by percent freezing during observation | Rebowe 2016 [41] | |
| Mood | Sigma1R knockout mice | Depression-like phenotype was noted | Hayashi 2011 [49] |
| Motor, cognitive deficiency | Cellular models of Huntington’s disease | mHtt (huntingtin fragment) protein downregulated Sigma1R expression in cultured PC6.3 neurons | Ryskamp 2019 [69] |
| Hyperactivity | Fmr1 KO2 mouse model of Fragile X-autism-related disorders model | ANAVEX 2-73 (blarcamesine) reversed Fmr1-KO2 hyperactivity in locomotor assays (number of squares crossed per unit time) | Rebowe 2016 [41] |
| Motor | SOD1/Sigma1R mouse model of ALS | ALS was exacerbated by disrupting MAM components, dysregulating calcium, and causing mitochondrial dysfunction leading to neuronal degradation | Watanabe 2016 [70] |
| Motor/Neuroprotection | Genetic linkage analysis and cellular expression of mutant protein | Sigma1R genetic variant was associated with ALS; expression of motor neuron cell line model resulted in loss of resistance to ER stress-induced apoptosis | Al Saif 2011 [71] |
| Motor/Neuroprotection | Genetic linkage analysis | Sigma1R mutations were associated with non-juvenile ALS without FTLD | Ulla 2015 [72] |
| Motor/Neuroprotection | Genetic linkage analysis | Sigma1R mutations were associated with nuclear aggregates, ER stress, and increased apoptosis | Li 2015 [73] |
| Motor | Genetic linkage analysis | Homozygous missense variant of SigmaR1 resulted in distal hereditary motor neuropathy and lower limb spasticity (Silver-like syndrome) | Horga 2016 [74] |
| Motor | Genetic linkage analysis | Non-polymorphic mutation in Sigma1R was associated with FTLD and ALS | Luty 2010 [75] |
| Motor | Sigma1R knockout mice | Vulnerability of S1R knockout mice to nigrostriatal axonal degradation was increased in a model of Parkinson’s disease | Ryskamp 2019 [69] |
Not an exhaustive list. ALS, amyotrophic lateral sclerosis; DEE, developmental and epileptic encephalopathy; ER, endoplasmic reticulum; FTLD, frontotemporal lobar degeneration; KO, knockout; MAM, mitochondria-associated membrane; Sigma1R, sigma-1 receptor.