The Evolution-Driven Signature of Parkinson’s Disease
Authors: Nico J. Diederich, Toshiki Uchihara, Sten Grillner, Christopher G. Goetz
Journal: Trends in Neurosciences (2020)

Evolutionarily based cellular vulnerability can explain clinical and pathological involvement of various structures in Parkinson's disease (PD).Neurons in PD-prone structures share similar features, including long and highly branched axons, spontaneous pacemaker spiking, and elevated mitochondrial oxidant stress. In humans, the metabolic demands in these cells are higher than in other species, due to human longevity and exceptionally large number of synapses per neuron.Neurons displaying vulnerability in PD share strikingly similar cellular phenotypes across various brain structures beyond the substantia nigra pars compacta, including the dorsal vagal motor nucleus, amygdala, locus coeruleus, pedunculopontine nucleus, raphe nuclei, diverse skin, and retinal or heart autonomic ganglia.These structures remain largely unchanged throughout evolution, and there is a mismatch between their relatively evolutionary conservation and the marked expansion of the human telencephalon.In PD, there are numerous clinical repercussions: gait automatization and subconscious blindsight are compromised; imprecise neuromodulatory tuning leads to emotional, autonomic, and sleep–wake dysregulation; ontogenetically primitive behaviours such as rapid eye movement sleep behaviour disorder re-emerge.Our model bridges from hierarchical concepts to evolutionarily driven connectomics and accounts for the variability and synchronicity of various clinical symptoms across anatomically separated networks. In this review, we approach Parkinson's disease (PD) in the context of an evolutionary mismatch of central nervous system functions. The neurons at risk have hyperbranched axons, extensive transmitter release sites, display spontaneous spiking, and elevated mitochondrial stress. They function in networks largely unchanged throughout vertebrate evolution, but now connecting to the expanded human cortex. Their breakdown is favoured by longevity. At the cellular level, mitochondrial dysfunction starts at the synapses, then involves axons and cell bodies. At the behavioural level, network dysfunctions provoke the core motor syndrome of parkinsonism including freezing and failed gait automatization, and non-motor deficits including inactive blindsight and autonomic dysregulation. The proposed evolutionary re-interpretation of PD-prone cellular phenotypes and of prototypical clinical symptoms allows a new conceptual framework for future research. In this review, we approach Parkinson's disease (PD) in the context of an evolutionary mismatch of central nervous system functions. The neurons at risk have hyperbranched axons, extensive transmitter release sites, display spontaneous spiking, and elevated mitochondrial stress. They function in networks largely unchanged throughout vertebrate evolution, but now connecting to the expanded human cortex. Their breakdown is favoured by longevity. At the cellular level, mitochondrial dysfunction starts at the synapses, then involves axons and cell bodies. At the behavioural level, network dysfunctions provoke the core motor syndrome of parkinsonism including freezing and failed gait automatization, and non-motor deficits including inactive blindsight and autonomic dysregulation. The proposed evolutionary re-interpretation of PD-prone cellular phenotypes and of prototypical clinical symptoms allows a new conceptual framework for future research. Parkinson's disease (PD) is the second most frequent neurodegenerative disease in humans. Age is the principal risk factor, with incidence rising exponentially above 60 years [1.de Lau L.M. Breteler M.M. Epidemiology of Parkinson's disease.Lancet Neurol. 2006; 5: 525-535Abstract Full Text Full Text PDF PubMed Scopus (2087) Google Scholar]. In a previous Personal View paper, we reviewed anatomical and physiological differences between the PD-susceptible structures in the human brain and their counterparts in other mammals [2.Diederich N.J. et al.Parkinson's disease: is it a consequence of human brain evolution?.Mov. Disord. 2019; 34: 453-459Crossref PubMed Scopus (5) Google Scholar]. In this review, we first explore the reasons for focal vulnerability of certain cell types. A unifying pattern of high energy demands at multiple levels crystallizes, based on salient studies that will be discussed in detail. We extend the review beyond the commonly accepted focus on dopaminergic cells by showing that there is also involvement of serotonergic, cholinergic, and noradrenergic neurons, all originating in the brainstem or the basal ganglia (BG). With this novel system approach, we link vulnerable networks within an argument related to evolution, based on works of comparative anatomy and clinical neurology. With the input of behavioural evolutionary sciences, we re-interpret key clinical PD syndromes as manifestations of dysfunctional or maladaptive archaic networks. We argue that the structures at risk modulate automated behaviours in response to environmental challenges, and we give salient clinical examples supporting this hypothesis. However, we draw attention to the fact that the available literature does not link this re-interpretation to all PD symptoms, especially when it comes to those appearing lately in the course of the disease. As the arguments develop, we hope to cement the concept that there may be an evolutionary mismatch within the human brain due to the dichotomy between areas (specifically the telencephalon) where cellular numbers and network complexity have increased markedly and areas of the brain that have largely remained static in terms of these indices. These data are closely linked to selective vulnerability of certain cell types and to the evolutionary rooting of PD syndromes. In 1997, Parent [3.Parent A. The brain in evolution and involution.Biochem. Cell Biol. 1997; 75: 651-667Crossref PubMed Google Scholar] stated that 'structures that appear early in the evolution are among the first to undergo involution in ageing diseases' and 'the neurodegenerative processes at play specifically target the most phylogenetically ancient components of the brain, including the SN.' But how? Based on immunohistochemical findings, Parent and co-workers suspected that characteristics of the axon are a key to understanding the degenerative process of human PD [4.Parent A. et al.Organization of the basal ganglia: the importance of axonal collateralization.Trends Neurosci. 2000; 23: 20-27Abstract Full Text PDF PubMed Google Scholar]. Indeed, the human substantia nigra pars compacta (SNc) projections have highly branched terminal regions with an extraordinary number of synaptic release sites. For one dopaminergic neuron reaching out to the human striatum this number has been estimated to be between 1 × 106 and 2.4 × 106, with highest values in neurons originating in the lateral part of the SNc [5.Bolam J.P. Pissadaki E.K. Living on the edge with too many mouths to feed: why dopamine neurons die?.Mov. Disord. 2012; 27: 1478-1483Crossref PubMed Scopus (0) Google Scholar, 6.Redgrave P. et al.Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease.Nat. Rev. Neurosci. 2010; 11: 760-772Crossref PubMed Scopus (523) Google Scholar, 7.Hernandez L.F. et al.Dopaminergic vulnerability in Parkinson disease: the cost of humans' habitual performance.Trends Neurosci. 2019; 42: 375-383Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In order to maintain the connections, axons develop a high degree of arborization: they become hyperbranched. Although these data suggest primarily an unfavourable ratio of SNc neurons to striatal and suprastriatal cortical neurons, it could also be that the degree of hyperbranchism as well as the number of synapses that one single SNc axon has to form in the human striatum goes up in a secondary, compensatory way when other SNc neurons succumb to the disease process or to old age. Anyhow, it has been estimated that the energy cost of axon potential propagation and synaptic release increases exponentially with hyperbranchism [8.Pissadaki E.K. Bolam J.P. The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson's disease.Front. Comput. Neurosci. 2013; 7: 13Crossref PubMed Scopus (124) Google Scholar] (Figure 1). When taking into account that the length of a single SNc dopamine (DA) neuron exceeds 4 m, it is instantly obvious that the bioenergetic demands associated with such abundant vesicular transmitter release are likely to be daunting [9.Attwell D. Laughlin S.B. An energy budget for signaling in the grey matter of the brain.J. Cereb. Blood Flow Metab. 2011; 21: 1133-1145Crossref Scopus (1690) Google Scholar,10.Sengupta B. et al.Information and efficiency in the nervous system – a synthesis.PLoS Comput. Biol. 2013; 9e1003157Crossref PubMed Scopus (0) Google Scholar]. Other neurons at risk in PD also have highly branched axons with thousands of transmitter release sites at telencephalic targets, although quantitative estimations as in the case of dopaminergic neuron are currently lacking. For instance, serotonergic neurons from the raphe nuclei have long and highly branched axons that innervate forebrain areas including the striatum [11.Deneris E. Gaspar P. Serotonin neuron development: shaping molecular and structural identities.Wiley Interdiscip. Rev. Dev. Biol. 2018; 7https://doi.org/10.1002/wdev.301Crossref PubMed Scopus (24) Google Scholar]. Pedunculopontine cholinergic neurons, locus coeruleus noradrenergic neurons, and lateral hypothalamic orexin neurons, all have long, highly branched axons that innervate the telencephalon (see [12.Uchihara T. et al.Propagation of Aβ, tau and α-synuclein pathology between experimental models and human reality: prions, propagons and propaganda.Acta Neuropathol. 2016; 131: 1-3Crossref PubMed Scopus (9) Google Scholar, 13.Mena-Segovia J. Bolam J.P. Rethinking the pedunculopontine nucleus: from cellular organization to function.Neuron. 2017; 94: 7-18Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 14.Uchihara T. Giasson B.I. Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.Acta Neuropathol. 2016; 131: 49-73Crossref PubMed Scopus (74) Google Scholar, 15.Parent M. Parent A. Relationship between axonal collateralization and neuronal degeneration in basal ganglia.J. Neural Transm. Suppl. 2006; 70: 85-88Google Scholar, 16.Visser A.K. et al.Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications.Eur. J. Nucl. Med. Mol. Imaging. 2011; 38: 576-591Crossref PubMed Scopus (24) Google Scholar] and Figure 2). Of note, the evolutionarily well-conserved melanopsin-containing ganglion cells in the retina also widely innervate various brain structures, including not only their primary target the suprachiasmatic nucleus but also the superior colliculus (SC) and the dorsal lateral geniculate nucleus [17.Berson D.M. et al.Phototransduction by retinal ganglion cells that set the circadian clock.Science. 2002; 295: 1070-1073Crossref PubMed Scopus (2051) Google Scholar,18.Hattar S. et al.Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity.Science. 2002; 295: 1065-1070Crossref PubMed Scopus (1606) Google Scholar]. Beyond this undeniable energy challenge, it has to be questioned how subtle gauging or calibration can be maintained in highly branched systems and how precise feedback should function. Adequate feedback seems to be maintained in early human life, but this is no more the case in PD, as clinically confirmed by less adequate tuning of movements, emotional expressions, and reactions [19.Bowers D. et al.Startling facts about emotion in Parkinson's disease: blunted reactivity to aversive stimuli.Brain. 2006; 129: 3356-3365Crossref PubMed Scopus (79) Google Scholar]. While efficiently adaptive to development, hyperbranching is at risk for breakdown with age, causing reversion to slower, coarser, and less adaptive behaviours, all characteristic features of PD (see Box 1 on other contributing, deleterious evolutionary mechanisms).Figure 2Hyperbranchism of Different Neuronal Networks at Risk for Involvement in Parkinson's Disease (PD).Show full caption(A) Wide-ranging axonal arborization of a GPi neuron (from [15.Parent M. Parent A. Relationship between axonal collateralization and neuronal degeneration in basal ganglia.J. Neural Transm. Suppl. 2006; 70: 85-88Google Scholar], with permission). The arrow points to the location of the cell body. The estimation of axonal varicosities is indicated in parentheses. Reconstruction from serial sections. (B) Melanopsin ganglion cells in the retina (from [31.Lax P. et al.Photosensitive melanopsin-containing retinal ganglion cells in health and disease: implications for circadian rhythms.Int. J. Mol. Sci. 2019; 20E3164Crossref PubMed Scopus (4) Google Scholar], with permission). The left representative drawings illustrate melanopsin plexus in a control subject, whereas the right drawings show the (reduced) melanopsin plexus in a PD patient. Individual melanopsin retinal ganglion cells are shown by different colours. (C) Wide-ranging connectivity of cholinergic neurons from the pedunculopontine nucleus (PPN) (from [13.Mena-Segovia J. Bolam J.P. Rethinking the pedunculopontine nucleus: from cellular organization to function.Neuron. 2017; 94: 7-18Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], with permission). Single-cell tracing studies are depicted in the left part. The PPN is represented by a shaded area. The main three axonal trajectories of cholinergic PPN neurons are an ascending dorsal stream, an ascending ventral stream, and a descending projection. (D) Schematic connectivity of the serotonergic neurons from the raphe nuclei (from [16.Visser A.K. et al.Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications.Eur. J. Nucl. Med. Mol. Imaging. 2011; 38: 576-591Crossref PubMed Scopus (24) Google Scholar], with permission). Both autoreceptors in the raphe nuclei (5-HT1A and 5-HT1B) and heteroreceptors or postsynaptic receptors in other areas are depicted by different colours. Abbreviations: Amyg, amygdala; Ant, anterior thalamus; CL, centrolateral thalamic nucleus; CM, centre median thalamic nucleus; FH, Forel field H; GiN, gigantocellular nucleus; GPi, internal segment of the globus pallidus; IC, inferior colliculus; PF, parafascicular nucleus; Pf, parafascicular thalamic nucleus; PnC, nucleus pontis caudalis; PnO, nucleus pontis oralis; PPN, pedunculopontine tegmental nucleus; RRA, retrorubral area; Rt, reticular thalamic nucleus; SC, superior colliculus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA/VL, ventral anterior/ventral lateral thalamic nuclei; VM, ventromedial thalamic nucleus; VTA, ventral tegmental area.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Box 1PD Deleterious Evolutionary MechanismsExaptation as Utensil for Network AdaptationEvolution has efficiently progressed by a 'recycling' approach with older circuits taking on new jobs. In this perspective the BGs have undergone what is called 'exaptation'. This is where an 'ancestral core unit is co-opted for multiple functions'. By changing the input and output targets, these loops simultaneously process different modalities and impact different physiological functions [72.Grillner S. Manira A.E. Current principles of motor control, with special reference to vertebrate locomotion.Physiol. Rev. 2020; 100: 271-320Crossref PubMed Scopus (12) Google Scholar]. One set of circuits thus handles emotional, cognitive, and motor functions in parallel, despite increasing complexity of the information input. Can exaptation also increase the vulnerability to the ageing process? Does it lead to higher vulnerability to genetic mutations and environmental toxins? In particular, does human 'frequent reliance on habitual performance' [7.Hernandez L.F. et al.Dopaminergic vulnerability in Parkinson disease: the cost of humans' habitual performance.Trends Neurosci. 2019; 42: 375-383Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] strain such systems?Antagonistic PleiotropyAntagonistic pleiotropy has been proposed to explain cognitive decline in old age [156.Magalhães J.P. Sandberg A. Cognitive aging as an extension of brain development: a model linking learning, brain plasticity, and neurodegeneration.Mech. Ageing Dev. 2005; 126: 1026-1033Crossref PubMed Scopus (32) Google Scholar]. The cellular phenotype of PD-prone neurons – pacemaker status, hyperbranching axons – functions well during young age, but succumbs later on. As human SNc dopaminergic neurons have to service larger striatal territories, they are able to transitorily – but not permanently – compensate efficiently by producing higher amounts of dopamine than, for instance, mouse neurons [157.Burbulla L.F. et al.Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.Science. 2017; 357: 1255-1261Crossref PubMed Scopus (199) Google Scholar]. Later on, this same mechanism enhances cellular vulnerability by a human-specific and time-dependent pathological cascade starting with increased mitochondrial oxidant stress and resulting, among others, in lysosomal dysfunction and aSyn accumulation [157.Burbulla L.F. et al.Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.Science. 2017; 357: 1255-1261Crossref PubMed Scopus (199) Google Scholar].Evolutionarily Imposed Trade-offsFar outreaching, energy-greedy neuronal networks may have been optimal for development during early life, but may become deleterious in late life. This dilemma has been crisply described as 'a tangle of trade-offs: energy versus function' [158.Maklakov A.A. Chapman T. Evolution of ageing as a tangle of trade-offs: energy versus function.Proc. Biol. Sci. 2019; 286: 20191604Crossref PubMed Scopus (7) Google Scholar]. In the nervous system the energy demands are enormous: with 2% of body volume the human brain consumes 20% of energy, with synapses requiring the highest portion (Figure 1). Among the energy trade-offs posited to explain telencephalization in humans, the 'expensive tissue' hypothesis has been among the most popular, as it proposes an evolutionary trade-off between the size of the human brain and the size of the human digestive tract, which has become considerably smaller than for a primate of human body size [159.Aiello L.C. Wheeler P. The expensive-tissue hypothesis: the brain and the digestive system in human and primate evolution.Curr. Anthropol. 1995; 36: 199-221Crossref Google Scholar,160.Navarrete A. et al.Energetics and the evolution of human brain size.Nature. 2011; 480: 91-93Crossref PubMed Scopus (0) Google Scholar]. Despite better digestibility of current human food, this places a burden on PD-prone enteric neurons. Other functional trade-offs directly challenge the BG. Among them, bipedal locomotion has to be mentioned. When comparing with quadrupedal walking in chimpanzees, human bipedalism is 75% less costly and attributable to extension of the hip and hindlimb [161.Sockol M.D. et al.Chimpanzee locomotor energetics and the origin of human bipedalism.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 12265-12269Crossref PubMed Scopus (181) Google Scholar]. However, at the BG level, it demands higher organizational complexity when coordinating forward locomotion. (A) Wide-ranging axonal arborization of a GPi neuron (from [15.Parent M. Parent A. Relationship between axonal collateralization and neuronal degeneration in basal ganglia.J. Neural Transm. Suppl. 2006; 70: 85-88Google Scholar], with permission). The arrow points to the location of the cell body. The estimation of axonal varicosities is indicated in parentheses. Reconstruction from serial sections. (B) Melanopsin ganglion cells in the retina (from [31.Lax P. et al.Photosensitive melanopsin-containing retinal ganglion cells in health and disease: implications for circadian rhythms.Int. J. Mol. Sci. 2019; 20E3164Crossref PubMed Scopus (4) Google Scholar], with permission). The left representative drawings illustrate melanopsin plexus in a control subject, whereas the right drawings show the (reduced) melanopsin plexus in a PD patient. Individual melanopsin retinal ganglion cells are shown by different colours. (C) Wide-ranging connectivity of cholinergic neurons from the pedunculopontine nucleus (PPN) (from [13.Mena-Segovia J. Bolam J.P. Rethinking the pedunculopontine nucleus: from cellular organization to function.Neuron. 2017; 94: 7-18Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], with permission). Single-cell tracing studies are depicted in the left part. The PPN is represented by a shaded area. The main three axonal trajectories of cholinergic PPN neurons are an ascending dorsal stream, an ascending ventral stream, and a descending projection. (D) Schematic connectivity of the serotonergic neurons from the raphe nuclei (from [16.Visser A.K. et al.Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications.Eur. J. Nucl. Med. Mol. Imaging. 2011; 38: 576-591Crossref PubMed Scopus (24) Google Scholar], with permission). Both autoreceptors in the raphe nuclei (5-HT1A and 5-HT1B) and heteroreceptors or postsynaptic receptors in other areas are depicted by different colours. Abbreviations: Amyg, amygdala; Ant, anterior thalamus; CL, centrolateral thalamic nucleus; CM, centre median thalamic nucleus; FH, Forel field H; GiN, gigantocellular nucleus; GPi, internal segment of the globus pallidus; IC, inferior colliculus; PF, parafascicular nucleus; Pf, parafascicular thalamic nucleus; PnC, nucleus pontis caudalis; PnO, nucleus pontis oralis; PPN, pedunculopontine tegmental nucleus; RRA, retrorubral area; Rt, reticular thalamic nucleus; SC, superior colliculus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA/VL, ventral anterior/ventral lateral thalamic nuclei; VM, ventromedial thalamic nucleus; VTA, ventral tegmental area. Exaptation as Utensil for Network Adaptation Evolution has efficiently progressed by a 'recycling' approach with older circuits taking on new jobs. In this perspective the BGs have undergone what is called 'exaptation'. This is where an 'ancestral core unit is co-opted for multiple functions'. By changing the input and output targets, these loops simultaneously process different modalities and impact different physiological functions [72.Grillner S. Manira A.E. Current principles of motor control, with special reference to vertebrate locomotion.Physiol. Rev. 2020; 100: 271-320Crossref PubMed Scopus (12) Google Scholar]. One set of circuits thus handles emotional, cognitive, and motor functions in parallel, despite increasing complexity of the information input. Can exaptation also increase the vulnerability to the ageing process? Does it lead to higher vulnerability to genetic mutations and environmental toxins? In particular, does human 'frequent reliance on habitual performance' [7.Hernandez L.F. et al.Dopaminergic vulnerability in Parkinson disease: the cost of humans' habitual performance.Trends Neurosci. 2019; 42: 375-383Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] strain such systems? Antagonistic Pleiotropy Antagonistic pleiotropy has been proposed to explain cognitive decline in old age [156.Magalhães J.P. Sandberg A. Cognitive aging as an extension of brain development: a model linking learning, brain plasticity, and neurodegeneration.Mech. Ageing Dev. 2005; 126: 1026-1033Crossref PubMed Scopus (32) Google Scholar]. The cellular phenotype of PD-prone neurons – pacemaker status, hyperbranching axons – functions well during young age, but succumbs later on. As human SNc dopaminergic neurons have to service larger striatal territories, they are able to transitorily – but not permanently – compensate efficiently by producing higher amounts of dopamine than, for instance, mouse neurons [157.Burbulla L.F. et al.Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.Science. 2017; 357: 1255-1261Crossref PubMed Scopus (199) Google Scholar]. Later on, this same mechanism enhances cellular vulnerability by a human-specific and time-dependent pathological cascade starting with increased mitochondrial oxidant stress and resulting, among others, in lysosomal dysfunction and aSyn accumulation [157.Burbulla L.F. et al.Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.Science. 2017; 357: 1255-1261Crossref PubMed Scopus (199) Google Scholar]. Evolutionarily Imposed Trade-offs Far outreaching, energy-greedy neuronal networks may have been optimal for development during early life, but may become deleterious in late life. This dilemma has been crisply described as 'a tangle of trade-offs: energy versus function' [158.Maklakov A.A. Chapman T. Evolution of ageing as a tangle of trade-offs: energy versus function.Proc. Biol. Sci. 2019; 286: 20191604Crossref PubMed Scopus (7) Google Scholar]. In the nervous system the energy demands are enormous: with 2% of body volume the human brain consumes 20% of energy, with synapses requiring the highest portion (Figure 1). Among the energy trade-offs posited to explain telencephalization in humans, the 'expensive tissue' hypothesis has been among the most popular, as it proposes an evolutionary trade-off between the size of the human brain and the size of the human digestive tract, which has become considerably smaller than for a primate of human body size [159.Aiello L.C. Wheeler P. The expensive-tissue hypothesis: the brain and the digestive system in human and primate evolution.Curr. Anthropol. 1995; 36: 199-221Crossref Google Scholar,160.Navarrete A. et al.Energetics and the evolution of human brain size.Nature. 2011; 480: 91-93Crossref PubMed Scopus (0) Google Scholar]. Despite better digestibility of current human food, this places a burden on PD-prone enteric neurons. Other functional trade-offs directly challenge the BG. Among them, bipedal locomotion has to be mentioned. When comparing with quadrupedal walking in chimpanzees, human bipedalism is 75% less costly and attributable to extension of the hip and hindlimb [161.Sockol M.D. et al.Chimpanzee locomotor energetics and the origin of human bipedalism.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 12265-12269Crossref PubMed Scopus (181) Google Scholar]. However, at the BG level, it demands higher organizational complexity when coordinating forward locomotion. Examination of the somatodendritic region of at-risk neurons gives additional insight into the factors that might drive vulnerability. The dopaminergic neurons of the ventral tier of the SNc are slow, autonomous pacemakers with broad action potentials and large oscillations in cytosolic Ca2+ concentration [20.Surmeier D.J. et al.Dopaminergic modulation of striatal networks in health and Parkinson's disease.Curr. Opin. Neurobiol. 2014; 29: 109-117Crossref PubMed Scopus (62) Google Scholar,21.Surmeier D.J. et al.Parkinson's disease is not simply a prion disorder.J. Neurosci. 2017; 37: 9799-9807Crossref PubMed Scopus (66) Google Scholar]. While facilitating the pacemaking process, the Ca2+ oscillations also drive mitochondrial oxidative phosphorylation and ATP production, by loading juxtaposed mitochondria with Ca2+. This feed-forward bioenergetic control mechanism appears to be phylogenetically old, as it is present in muscle as well [22.Balaban R.S. Domestication of the cardiac mitochondrion for energy conversion.J. Mol. Cell. Cardiol. 2009; 46: 832-841Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. The mechanism ensures that sustained synaptically driven activity in dopaminergic neurons does not fail because of ATP depletion. This is critical in the BG because even short periods of inactivity in dopaminergic neurons would cause suppression in ongoing goal-directed movements, with possibly dire consequences to the organism's survival. Similarly, noninterrupted activity is crucial for other systems, including those maintaining circadian rhythms, preparedness in the form of arousal changes, and fight and flee responses or active avoidance behaviour [13.Mena-Segovia J. Bolam J.P. Rethinking the pedunculopontine nucleus: from cellular organization to function.Neuron. 2017; 94: 7-18Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,23.Hormigo S. et al.Circuits that mediate expression of signalled active avoidance converge in the pedunculopontine tegmentum.J. Neurosci. 2019; 39: 4576-4594Crossref PubMed Scopus (0) Google Scholar]. The feed-forward bioenergetic control system comes at a cost, however, when the induced oxidant stress diminishes the function of mitochondrial Complex I and increases mitochondrial damage and mitophagy [24.Grünewald A. et al.Mitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons.Ann. Neurol. 2016; 79: 366-378Crossref PubMed Scopus (0) Google Scholar]. When reaching a critical tipping point, PD-vulnerable neurons (at different sites) go over a bioenergetic 'cliff', become senescent, and die. In this context, it has to be mentioned that in the healthy condition the basal rate of oxidative phosphorylation in dopaminergic SNc neurons is already at the near maximal rate sustainable by the mitochondrial network and that the most actively involved mitochondria are located at the most extended arborizations