Fig. 1

Pridopidine promotes BDNF/TrkB signaling and restores ER calcium levels in the corticostriatal pathway. a Shown is a schematic representation of the motor circuit in mammals. Motor cortical neurons project to the striatum and form excitatory (glutamate, green line) synapses with D1 and D2 receptor-expressing neurons (D1 and D2, blue box). Inhibitory D1 receptor-expressing neurons make GABAergic connections (GABA, red line) with the pars reticulata of the substantia nigra (SNr). In contrast, D2 receptor-expressing neurons follow an indirect pathway and send GABAergic projections to the external segment of the globus pallidus (GPe). In turn, GABAergic neurons of the GPe project to the subthalamic nucleus (STN), and excitatory STN neurons send efferents to the SNr GABAergic projections that innervate thalamus, and the thalamus completes the basal ganglia-thalamocortical circuitry by sending excitatory projections to the motor cortex. b In the WT striatum, the huntingtin (Htt) protein facilitates axonal transport of synaptic vesicles carrying brain-derived neurotrophic factor (BDNF) and glutamate to the active zone of cortical neurons. Released glutamate and BDNF bind to their targets on the postsynaptic density of striatal neurons, including N-methyl-D-aspartate (NMDA) receptors and tropomyosin receptor kinase B (TrkB) receptors, respectively. c In Huntington disease, mutant Htt (mHtt) interferes with the axonal transport process, disrupting normal release of BDNF and consequently TrkB signaling in the striatum. In addition, endoplasmic reticulum (ER) calcium is also perturbed in the striatum during HD progression. d Shown is a proposed mechanism of action for pridopidine in the corticostriatal pathway. Treatment with pridopidine has been previously shown to improve both sigma 1 receptor (σ1r)-dependent BDNF release in neuroblastoma cells, increase striatal BDNF levels in HD mice and restore proper ER levels of Ca2+ via direct activation of σ1r in cortical and striatum co-cultures