Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor.

Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor.

Publication date: May 17, 2019

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT), translated into a Huntingtin protein with a polyglutamine expansion. There is preferential loss of medium spiny neurons within the striatum and cortical pyramidal neurons. Pridopidine is a small molecule showing therapeutic potential in HD preclinical and clinical studies. Pridopidine has nanomolar affinity to the sigma-1 receptor (sigma-1R), which is located predominantly at the endoplasmic reticulum (ER) and mitochondrial associated ER membrane, and activates neuroprotective pathways. Here we evaluate the neuroprotective effects of pridopidine against mutant Huntingtin toxicity in mouse and human derived in vitro cell models. We also investigate the involvement of the sigma-1 receptor in the mechanism of pridopidine. Pridopidine protects mutant Huntingtin transfected mouse primary striatal and cortical neurons, with an EC50 in the mid nanomolar range, as well as HD patient-derived induced pluripotent stem cells (iPSCs). This protection by pridopidine is blocked by NE-100, a purported sigma-1 receptor antagonist, and not blocked by ANA-12, a reported TrkB receptor antagonist. 3PPP, a documented sigma-1 receptor agonist, shows similar neuroprotective effects. Genetic knock out of the sigma-1 receptor dramatically decreases protection from pridopidine and 3PPP, but not protection via brain derived neurotrophic factor (BDNF). The neuroprotection afforded by pridopidine in our HD cell models is robust and sigma-1 receptor dependent. These studies support the further development of pridopidine, and other sigma-1 receptor agonists as neuroprotective agents for HD and perhaps for other disorders.

Eddings, C.R., Arbez, N., Akimov, S., Geva, M., Hayden, and Ross, C.A. Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. 06498. 2019 Neurobiol Dis.

Concepts Keywords
Affinity Neurodegeneration
Agonist Neuroprotection
Antagonist Huntington’s disease
BDNF Huntingtin
Cortical Neurology
EC50 Organ systems
Endoplasmic Reticulum Branches of biology
ER
Huntingtin
Huntington
Medium Spiny Neurons
Mitochondrial Membrane
Mutant
Nanomolar
Neurodegenerative
Neurons
Neuroprotection
Neuroprotective
Pluripotent
Polyglutamine Expansion
Pyramidal Neurons
Sigma 1 Receptor
Small Molecule
Striatal
Striatum
Toxicity
Transfected
TrkB Receptor

Semantics

Type Source Name
disease MESH development
gene UNIPROT BDNF
pathway BSID Brain derived neurotrophic factor
gene UNIPROT NTRK2
gene UNIPROT HTT
disease DOID neurodegenerative disease
disease MESH neurodegenerative disease
drug DRUGBANK Pridopidine

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