Na+ leak-current channel (NALCN) at the junction of motor and neuropsychiatric symptoms in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a debilitating movement disorder often accompanied by neuropsychiatric symptoms that stem from the loss of dopaminergic function in the basal ganglia and altered neurotransmission more generally. Akinesia, postural instability, tremors and frozen gait constitute the major motor disturbances, whereas neuropsychiatric symptoms include altered circadian rhythms, disordered sleep, depression, psychosis and cognitive impairment. Evidence is emerging that the motor and neuropsychiatric symptoms may share etiologic factors. Calcium/ion channels (CACNA1C, NALCN), synaptic proteins (SYNJ1) and neuronal RNA-binding proteins (RBFOX1) are among the risk genes that are common to PD and various psychiatric disorders. The Na+ leak-current channel (NALCN) is the focus of this review because it has been implicated in dystonia, regulation of movement, cognitive impairment, sleep and circadian rhythms. It regulates the resting membrane potential in neurons, mediates pace-making activity, participates in synaptic vesicle recycling and is functionally co-localized to the endoplasmic reticulum (ER)—several of the major processes adversely affected in PD. Here, we summarize the literature on mechanisms and pathways that connect the motor and neuropsychiatric symptoms of PD with a focus on recurring relationships to the NALCN. It is hoped that the various connections outlined here will stimulate further discussion, suggest additional areas for exploration and ultimately inspire novel treatment strategies.