Sigma‐2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain‐derived α‐synuclein

Preclinical studies support that S2R small molecule modulators can rescue biological processes that are impaired in neurodegenerative diseases.

“Preclinical studies support that S2R small molecule modulators can rescue biological processes that are impaired in neurodegenerative diseases [2,3,4,5].”

Support for targeting S2R derives from α-synuclein binding to PrPc and the finding that S2R modulators block α-synuclein oligomer toxicity in neurons.

“Support for targeting the S2R derives from α-synuclein binding to PrPc [42], and the finding that S2R modulators block α-synuclein oligomer toxicity in neurons [4]”

S2R modulators have been shown to ameliorate amyloid-β oligomer and α-synuclein oligomer-mediated deficits in neuronal trafficking.

“Indeed, S2R modulators have been shown to ameliorate amyloid-β oligomer and α-synuclein oligomer-mediated deficits in neuronal trafficking [2,3,4]”

Some small molecule modulators of S2R, such as siramesine and SV119, trigger the induction of autophagy, while other S2R modulators such as CT2168 can restore α-synuclein oligomer-induced deficits in lysosomal-associated membrane protein 2A levels back to healthy control levels in neurons.

“Some small molecule modulators of S2R, such as siramesine and SV119, trigger the induction of autophagy [118,120], while other S2R modulators such as CT2168 can restore α-synuclein oligomer-induced deficits in lysosomal-associated membrane protein 2A levels, an indirect marker of autophagy, back to healthy control levels in neurons [4].”

α-Synuclein oligomers induce cellular stress responses, including aberrant autophagy-lysosome pathways, dysregulation of lipid metabolism, and a reduction in membrane trafficking.

“α-Synuclein oligomers are known to induce cellular stress responses, including aberrant autophagy-lysosome pathways [161,162], dysregulation of lipid metabolism [163,164], and a reduction in membrane trafficking [4].”

Given that PGRMC1 and S2R can regulate proteins and processes underlying α-synuclein oligomer toxicity, compounds that bind to S2R and block α-synuclein binding and/or internalization are expected to be disease-modifying.

“Given that PGRMC1 and S2R can regulate proteins and processes underlying α-synuclein oligomer toxicity, compounds that bind to S2R and block α-synuclein binding and/or internalization are expected to be disease-modifying [4].”

α-Synuclein oligomers bind to neurons in culture and are internalized; with addition of an S2R modulator, the binding and thus internalization of the α-synuclein oligomers are inhibited.

“α-Synuclein oligomers were found to bind to neurons in culture and are internalized (Figure 7 [4]). With the addition of an S2R modulator, the binding and thus internalization of the α-synuclein oligomers are inhibited (Figure 7 [4]).”

Given the ability of S2R modulators to rescue both amyloid-β oligomer and α-synuclein oligomer deficits, there is promise that S2R may be beneficial in patients with dementia with Lewy bodies.

“Given the ability of S2R modulators to rescue both amyloid-β oligomer and α-synuclein oligomer deficits [2,3,4,64], there is promise that S2R may be beneficial in patients with dementia with Lewy bodies.”

Neuronal pathology in α-synucleinopathies includes deficits in membrane trafficking and upregulation of lysosomal-associated membrane protein-2A, a protein critically required for chaperone-mediated autophagy.

“More specifically, neuronal pathology observed in α-synucleinopathies includes deficits in membrane trafficking and an upregulation in lysosomal-associated membrane protein-2A, a protein critically required for chaperone-mediated autophagy [4].”