Role of the Central Cholinergic Nervous System in Motor and Non-Motor Symptoms of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder that is characterized by both motor and non-motor symptoms. Although dopamine agonists have been demonstrated to be efficacious in the treatment of motor symptoms, their capacity to enhance non-motor symptoms remains constrained. This suggests that additional neurotransmitter systems may be involved in the pathogenesis of PD-related symptoms. The cholinergic nervous system plays a pivotal role in the central nervous system, with various projection systems associated with diverse functions, including but not limited to learning, memory, attention, posture, balance, eye movement control, and adaptation. Nevertheless, the role of the cholinergic nervous system in the motor and non-motor impairments associated with PD remains uncertain. This review elucidates the location, projection, receptors, and effects of central cholinergic systems, as well as their role in both the motor symptoms and non-motor symptoms of PD. Additionally, it examines the crosstalk between cholinergic systems and dopaminergic systems in PD pathology. A deeper comprehension of the fundamental mechanisms of the cholinergic system in PD may facilitate the development of novel therapeutic strategies.

Keywords: Parkinson’s disease; acetylcholine; cholinergic system; dopamine agonists.; motor symptoms; non-motor symptoms.

Fig. (1)

The distribution, projections, and role of the cholinergic system in the central nervous system. (A) The composition of the BFCN projection system and its neural projections within the brain. (B) The PPN/LDT and MVN-cerebellar cholinergic system, including their projection into the brain and the distribution of cholinergic interneurons (ChIs) in the brain. The red dots depicted in the striatum, nucleus accumbens, and cerebral cortex signify ChIs. In contrast, the red arrows illustrate the connections between these ChIs and other neuronal populations within these nuclei.

Fig. (2)

The structural and component characteristics of the AChR. (A) Schematic representation of mAChRs illustrates its seven transmembrane domains (TM1-TM7) that traverse the lipid bilayer, along with their primary signaling pathways. M1R, M3R, and M5R are coupled with Gq proteins, whereas M2R and M4R are associated with Gi proteins. (B) The illustration depicts representative configurations of nAChR subunits in a pentameric configuration around a cation-permeable pore, which is filled with water. The most prevalent nAChRs in the brain are heterooligomeric α4β2 nAChRs and homo-oligomeric α7 nAChRs. (C) The transmembrane topology of nAChR subunits is characterized by a linear structure comprising four transmembrane domains (TM1-TM4) that traverse the lipid bilayer. Abbreviations: DAG, diacylglycerol; IP3, inositol triphosphate; AC, adenylyl cyclase; PLC, phospholipase A.