Parkinson's disease: Is it a consequence of human brain evolution?

Although experimental lesions to the dopaminergic system lead to Parkinson's disease (PD)-like motor symptoms in vertebrates extending from lamprey to primates,1 parkinsonism does not occur naturally in any species other than man. Aged nonhuman primates may show impaired fine motor control and reduced home cage activity, but these deficits are not sensitive to levodopa administration and are not accompanied by Lewy body (LB) burden.2 But why should PD be an exclusively human disease? One possibility is that the dramatic expansion of the telencephalon, particularly the neocortex, in humans creates a significant burden on subcortical circuits with which the telencephalon interacts, leading to increased vulnerability to aging, genetic mutations associated with PD, and environmental toxins. The human brain is approximately 3 times larger than that expected from a plot of brain weight against body size for nonhuman primates (Fig. 1A).3 This expansion concerns largely telencephalic structures.3 Expansion of the prefrontal cortex has been examined in detail, but there is ongoing debate on mechanistic aspects.4, 5 In comparison to other primates, molecular and cellular reorganization of neural circuitries in humans may be crucial.6 The relative growth of the human cerebral cortex may have been attributed to relaxed genetic control and the shift in the human diet from exclusively plants to a mixture of plants and nutritionally dense animal tissue, which allowed the metabolic demands of the cerebral cortex to be met without expanding the digestive tract.7, 8 Telencephalization has had obvious advantages for humans. Triggering neurodegeneration has been proposed as a downside9 to this growth. Could this telencephalic expansion be particularly detrimental for subcortical structures that interact with the cortex but have not grown commensurately? The basal ganglia (BG) blueprint arose nearly 500 million years ago and has been preserved throughout vertebrate phylogeny (Fig. 1B).10 This network helps make goal-directed behavior and habits rapid and “automatic.” When the BG is impaired, control becomes slower and less efficient; moreover, the ability to generate rapid, stimulus-driven, habitual motor sequences is largely lost.11 The largest of the BG nuclei is the striatum; it integrates information from other telencephalic structures—principally the cerebral cortex—about motor plans, internal motivational and affective states, and the external environment. Striatal activity regulates the BG interface nuclei, which then modulate other brain regions controlling movement and thought.12 The SNc is a key part of the BG circuit. The widely arborizing axons of these neurons innervate all parts of the BG, but have a particularly dense innervation of the striatum.13 Striatal processing of cortical signals depends upon this dopaminergic innervation, because it provides critical information about the outcome of actions and ongoing movement.14 Although ontogenetically the striatum is part of the telencephalon, in the course of human evolution, neocortical growth has been 5 times that of striatum.15 In fact, human striatal volume is significantly below predicted values from anthropoids (Fig. 1C). One way in which the striatum may have dealt with this “involution” is by “exaptation,” where ancestral circuits take on new jobs (Fig. 1E). Another part of the BG that has not kept pace with the cerebral cortex is the SNc. In humans, the number of SNc dopaminergic neurons per unit striatal volume is roughly one tenth that in a rodent.16 This means an individual SNc dopaminergic neuron innervates a much greater volume in humans. In humans, it is estimated that a single SNc axon may form 1 to 2 million synapses in the striatum—an order of magnitude greater than the number in a rodent.16 This extraordinary growth may be crucial to pathogenesis, given that the axon is widely thought to be the most vulnerable part of the human SNc dopaminergic neuron, beginning to degenerate in the earliest stages of PD. Other vulnerable parts of the brain also appear to have been “left behind.” This concerns the evolutionarily oldest parts of the amygdala such as the basal, accessory basal, and central amygdaloid nuclei; the human central amygdaloid nucleus is estimated to be one third the size expected of a hominoid.17 In contrast, the evolutionarily younger lateral amygdaloid nucleus is almost 40% larger than expected. Of note: The cells of the older amygdalar nuclei are densely branched spiny neurons similar to the striatum, whereas the younger amygdalar nuclei contain pyramidal-like neurons similar to the cerebral cortex.18 When compared to the cerebral cortex, the total number of locus coeruleus (LC) neurons is substantially lower than expected in humans (Fig. 1D).19 The olfactory bulb is approximately 30% as large as it should be for a primate brain.20 Many of the other neurons at-risk in PD—basal forebrain cholinergic neurons, pedunculopontine cholinergic neurons, intralaminar thalamic glutamatergic neurons, raphe serotonergic neurons, and lateral hypothalamic orexin neurons—also have long, highly branched axons that innervate the cerebral cortex or regions that have been affected by the relative growth of the telencephalon.21 How might a highly branched, unmyelinated axon with millions of transmitter release sites increase a neuron's risk in PD? Most of the thinking around this point has focused on the bioenergetic demands associated with sustaining the electrochemical gradients necessary for spike propagation and the machinery necessary for neurotransmission. The proposition that mitochondrial oxidant stress is a driver of pathogenesis in PD is consistent with three other key pieces of evidence. First, genetic mutations that increase mitochondrial oxidant stress or impair mitochondrial quality control lead to early-onset forms of PD. Second, environmental toxins that impair mitochondrial function increase the risk of PD. Third, mitoc