Pedunculopontine Nucleus Degeneration Contributes to Both Motor and Non-Motor Symptoms of Parkinson’s Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.

Effects of pedunculopontine nucleus cholinergic lesion on gait and dyskinesia in hemiparkinsonian rats

“…The PPN is involved in drug-induced motor stereotypy resembling that observed in dyskinesia (Chambers et al, 2020;Inglis et al, 1994). For instance, PPN lesion or cholinergic antagonism exacerbates amphetamine-induced motor stereotypy and dyskinesia (Chambers et al, 2019;Mathur et al, 1997).…”

“…Additionally, anywhere from 40% to 70% of pedunculopontine nucleus (PPN), acetylcholine (ACh) neurons are lost, contributing to PD akinesia, gait, and postural instability (Bohnen et al, 2009(Bohnen et al, , 2013(Bohnen et al, , 2019Hirsch et al, 1987;Jellinger, 1988;Rinne et al, 2008;Zweig et al, 1989). PPN neurons may also be involved in L-DOPA-and DAagonist-mediated behaviors like motor improvement and dyskinesia (Bastide et al, 2014;Chambers et al, 2019Chambers et al, , 2020Inglis et al, 1994). Despite evidence of PPN involvement in motor deficits and freezing (MacLaren et al, 2014(MacLaren et al, , 2018Pienaar et al, 2015;Sharma et al, 2020;Xiao et al, 2017), a causal role for PPN cholinergic neurons on specific gait parameters, L-DOPA efficacy, and dyskinesia remains unproven.…”

“…The PPN likely regulates gait through both ascending and descending efferents (Chambers et al., 2020). The PPN is functionally divided into a rostral portion which projects to motor structures such as the striatum, substantia nigra pars compacta, and thalamus, and a caudal portion which projects primarily to structures involved in reward such as the ventral tegmental area (Dautan et al., 2014; Xiao et al., 2016).…”

Gait and balance disturbances are common in young urbanites and associated with cognitive impairment. Air pollution and the historical development of Alzheimer's disease in the young

“…Gait, equilibrium and postural disorders are linked to neurological and neurodegenerative pathologies. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 Gait is a complex activity requiring the activation of the cerebral cortex, basal ganglia, cerebellum, brainstem, spinal cord and the musculoskeletal system. 14 , 15 , 16 , 17 , 18 Independent papers by Kaoru Takakusaki, Klaus Jahn and Anat Mirelman et al, 14 , 15 , 16 extensively discuss human locomotion and the key regions associated with gait and posture i.e., the mesencephalic locomotor region (MLR) and its projections to the pontomedullary reticular formation; the subthalamic locomotor region (SLR) and the cerebellar locomotor region (CLR).…”

On the Right Track to Treat Movement Disorders: Promising Therapeutic Approaches for Parkinson’s and Huntington’s Disease

“…Nevertheless, this does not explain the effect of SCS on gait and postural dysfunction. The participation of the brainstem, specifically the pedunculopontine nucleus (PPN), has been suggested, given its connection with different structures involved in the motor system, summarized by Chambers et al ( 2019 ).…”