The pedunclopontine nucleus and Parkinson's disease

Abstract

In the last decade, scientific and clinical interest in the pedunculopontine nucleus (PPN) has grown dramatically. This growth is largely a consequence of experimental work demonstrating its connection to the control of gait and of clinical work implicating PPN pathology in levodopa-insensitive gait symptoms of Parkinson's disease (PD). In addition, the development of optogenetic and chemogenetic approaches has made experimental analysis of PPN circuitry and function more tractable. In this brief review, recent findings in the field linking PPN to the basal ganglia and PD are summarized; in addition, an attempt is made to identify key gaps in our understanding and challenges this field faces in moving forward.

Determinants of seeding and spreading of α-synuclein pathology in the brain

“…Both of these proteins are more highly expressed in PPN glutamatergic and GABAergic neurons than in CNs (60). PPN CNs exhibit significant oscillations in intracellular Ca 2+ concentration that resemble those found in LP-vulnerable dopaminergic neurons in the ventral tier of the substantia nigra (52,61). Additional studies will be required to determine which (if any) of these factors governs selective uptake of PFFs by PPN CNs.…”

“…One factor that is well known to enhance aSYN pathology is the expression of aSYN itself. High levels of endogenous expression promote pathology (19,52). As aSYN is largely a synaptic protein (53), neuronal expression levels should scale with axonal arbor size.…”

Calcium, Bioenergetics, and Parkinson’s Disease

“…Another vulnerable population of cholinergic neurons are in the pedunculopontine nucleus (PPN). PPN neurons are heterogeneous, being comprised of glutamatergic, cholinergic, and GABAergic neurons [ 339 , 340 , 341 ]. Cholinergic neurons are the most vulnerable [ 342 , 343 , 344 ].…”

What’s wrong with the striatal cholinergic interneurons in Parkinson’s disease? Focus on intrinsic excitability

“…Anticholinergic actions at extrastriatal sites impair short term memory and frontal lobe function in patients and may exacerbate gait and postural deficits (Katzenschlager et al., 2003; Perez‐Lloret & Barrantes, 2016). Importantly, there is evidence that cholinergic neurons in the pedunculopontine tegmental nucleus and basal forebrain degenerate in patients and animal models of PD (Hirsch, Graybiel, Duyckaerts, & Javoy‐Agid, 1987; Zweig, Jankel, Hedreen, Mayeux, & Price, 1989; Shinotoh et al., 1999; Villalba, Pare, Lee, Lee, & Smith, 2019; Tubert, Galtieri, & Surmeier, 2019), leading to reduced acetylcholine levels at the cerebral cortex and thalamus that contribute to the cognitive and gait deficits observed in patients (Düzel et al., 2010; Fernández et al., 2011; Hall, Echt, Wolf, & Rogers, 2011; Sarter, Albin, Kucinski, & Lustig, 2014; Tubert et al., 2019; Wolf et al., 2014). Brain imaging studies support the existence of such hypocholinergic state in the thalamus and cortex (Bohnen et al., 2012, 2015; Bohnen, Müller, & Frey, 2017; Kim, Müller, Bohnen, Sarter, & Lustig, 2017; Müller et al., 2013; Ray et al., 2018).…”