Targeting the cholinergic system in Parkinson’s disease

Abstract

Motor control in the striatum is an orchestra played by various neuronal populations. Loss of harmony due to dopamine deficiency is considered the primary pathological cause of the symptoms of Parkinson’s disease (PD). Recent progress in experimental approaches has enabled us to examine the striatal circuitry in a much more comprehensive manner, not only reshaping our understanding of striatal functions in movement regulation but also leading to new opportunities for the development of therapeutic strategies for treating PD. In addition to dopaminergic innervation, giant aspiny cholinergic interneurons (ChIs) within the striatum have long been recognized as a critical node for balancing dopamine signaling and regulating movement. With the roles of ChIs in motor control further uncovered and more specific manipulations available, striatal ChIs and their corresponding receptors are emerging as new promising therapeutic targets for PD. This review summarizes recent progress in functional studies of striatal circuitry and discusses the translational implications of these new findings for the treatment of PD.

Effects on Dopaminergic Neurons are Secondary in COX-Deficient Locomotor Dysfunction in <i>Drosophila</i>

“…Mitochondrial dysfunction has also been widely proposed as an instrumental factor in a variety of neurodegenerative diseases (Smith et al, 2019;Lim et al, 2020). Neuronal classes other than DA neurons have recently been implicated in neurodegenerative disease in humans (Liu, 2020). Our findings provide a possible model whereby mitochondrial dysfunction in such cells might be an underlying factor in the pathology, operating long before overt neurodegeneration manifests.…”

Effects on Dopaminergic Neurons Are Secondary in COX-Deficient Locomotor Dysfunction in Drosophila

“…Mitochondrial dysfunction has also been widely proposed as an instrumental factor in a variety of neurodegenerative diseases ( Smith et al, 2019 ; Lim et al., 2020 ). Neuronal classes other than DA neurons have recently been implicated in neurodegenerative disease in humans ( Liu, 2020 ). Our findings provide a possible model whereby mitochondrial dysfunction in such cells might be an underlying factor in the pathology, operating long before overt neurodegeneration manifests.…”

Novel Pharmacotherapies in Parkinson’s Disease

“…Indeed, a potential role of nAChRs in high-order cognitive processing has been suggested (Koukouli and Changeux 2020 ). Therapeutic potential for selective nAChR agonists in various neuropsychiatric and neurodegenerative disorders including PD (Quik et al 2019 ; Tizabi et al 2019 ; Liu 2020 ), depression (Gandelman et al 2018 ; Tizabi et al 2019 ; Conti et al 2020 ), mild cognitive impairment or Alzheimer’s disease (Vega et al 2019 ; Azimi et al 2020 ; Hahn et al 2020 ; Koukouli and Changeux 2020 ), ischemia (Han et al 2020b ), schizophrenia (Terry and Callahan, 2020 ), pain (Bagdas et al 2018 ), as well as energy balance (Seoane-Collazo et al 2021 ) have been proposed. Given that there is a relatively high comorbid existence between depression and PD, a nicotinic intervention may have the added advantage of addressing both issues at the same time (Tizabi et al 2019 ).…”

“…Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder, is associated with loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) that leads to striatal dopamine (DA) deficiency (Blesa and Przedborski 2014 ; Hustad and Aasly 2020 ; Liu 2020 ; Simon et al 2020 ). This loss of dopaminergic neurons results in motor deficits characterized by the following: akinesia, rigidity, resting tremor, and postural instability, as well as nonmotor symptoms that might also involve other neurotransmitter systems including the cholinergic system (Perez 2015 ; Mirelman et al 2019 ; Quik et al 2019 ; Stoker and Barker 2020 ).…”