Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan 15;10:1494.
doi: 10.3389/fphar.2019.01494. eCollection 2019.

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

Free PMC article

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

Nicole Elaine Chambers et al. Front Pharmacol. .
Free PMC article


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.

Keywords: Parkinson’s disease; REM sleep behavior disorder; gait deficits; neurodegeneration; non-motor symptoms; pedunculopontine nucleus; pharmacology.


Figure 1
Figure 1
Efferent PPN projections and putative involvement in PD symptoms. (A) PPN efferents to brain areas involved in PD motor symptoms, (B) PPN efferents contacting brain areas involved in PD-related sleep disturbances. STR, Striatum; THAL, Thalamus; STN, Sub-thalamic nucleus; GPi, Globus Pallidus Interna; DRN, Dorsal Raphe Nucleus; Med, Medulla; SNr, Substantia Nigra Pars Reticulata; SNc, Substantia Nigra Pars Compacta; H-Thal, Hypothalamus; (Images modified from serviermedical art

Similar articles

See all similar articles


    1. Ahlskog J. E., Muenter M. D. (2001). Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Movement Disord. 16, 448–458. 10.1002/mds1090 - DOI - PubMed
    1. Assous M., Tepper J. M. (2019). Excitatory extrinsic afferents to striatal interneurons and interactions with striatal microcircuitry. Eur. J. Neurosci. 49 (5), 593–603. 10.1111/ejn.13881 - DOI - PMC - PubMed
    1. Austin M., Rice P., Mann J., Arango V. (1995). Localization of corticotropin-releasing hormone in the human locus coeruleus and pedunculopontine tegmental nucleus: an immunocytochemical and in situ hybridization study. Neuroscience 64, 713–727. 10.1016/0306-4522(94)00420-A - DOI - PubMed
    1. Baghdoyan H. A., Rodrigo-Angulo M. L., McCarley R. W., Hobson J. A. (1984). Site-specific enhancement and suppression of desynchronized sleep signs following cholinergic stimulation of three brainstem regions. Brain Res. 306, 39–52. 10.1016/0006-8993(84)90354-8 - DOI - PubMed
    1. Bakker M., De Lange F. P., Helmich R. C., Scheeringa R., Bloem B. R., Toni I. (2008). Cerebral correlates of motor imagery of normal and precision gait. NeuroImage 41, 998–1010. 10.1016/j.neuroimage.2008.03.020 - DOI - PubMed

LinkOut - more resources