Developmental pathways linked to the vulnerability of adult midbrain dopaminergic neurons to neurodegeneration

Abstract

The degeneration of dopaminergic and other neurons in the aging brain is considered a process starting well beyond the infantile and juvenile period. In contrast to other dopamine-associated neuropsychiatric disorders, such as schizophrenia and drug addiction, typically diagnosed during adolescence or young adulthood and, thus, thought to be rooted in the developing brain, Parkinson's Disease (PD) is rarely viewed as such. However, evidences have accumulated suggesting that several factors might contribute to an increased vulnerability to death of the dopaminergic neurons at an already very early (developmental) phase in life. Despite the remarkable ability of the brain to compensate such dopamine deficits, the early loss or dysfunction of these neurons might predispose an individual to suffer from PD because the critical threshold of dopamine function will be reached much earlier in life, even if the time-course and strength of naturally occurring and age-dependent dopaminergic cell death is not markedly altered in this individual. Several signaling and transcriptional pathways required for the proper embryonic development of the midbrain dopaminergic neurons, which are the most affected in PD, either continue to be active in the adult mammalian midbrain or are reactivated at the transition to adulthood and under neurotoxic conditions. The persistent activity of these pathways often has neuroprotective functions in adult midbrain dopaminergic neurons, whereas the reactivation of silenced pathways under pathological conditions can promote the survival and even regeneration of these neurons in the lesioned or aging brain. This article summarizes our current knowledge about signaling and transcription factors involved in midbrain dopaminergic neuron development, whose reduced gene dosage or signaling activity are implicated in a lower survival rate of these neurons in the postnatal or aging brain. It also discusses the evidences supporting the neuroprotection of the midbrain dopaminergic system after the external supply or ectopic expression of some of these secreted and nuclear factors in the adult and aging brain. Altogether, the timely monitoring and/or correction of these signaling and transcriptional pathways might be a promising approach to a much earlier diagnosis and/or prevention of PD.

Keywords: Parkinson’s disease; dopamine; maintenance; mesencephalon; neuroprotection; survival.

Figure 1

The human mDA system in the adult healthy and PD brain. (A) Sagittal view (upper) and enlarged parasagittal section (lower) of the adult human brain, showing the location of the cell bodies (ovals) from the A8 (RRF, pink), A9 (SNc, green), and A10 (VTA, blue) mDA clusters in the brainstem, and their projections (arrows) to the limbic areas (mesolimbic pathway), striatum (nigrostriatal pathway) and PFC (mesocortical pathway). Note that both the VTA and RRF DA neurons project to limbic areas in the mesolimbic pathway. Labeling of other structures (hypothalamus, etc.) and limbic regions, such as the NAc, olfactory tubercle, amygdala, septum, cingulate and perirhinal cortex, in this sagittal view have been omitted for clarity. (B,C) Cross-sections at the levels of the dotted lines in (A) through the human forebrain (B) and midbrain/brainstem (C) depicting the location of the projection areas and cell bodies, respectively, of the human SNc DA subset. In the healthy human brain (left side), dark pigmented (neuromelanin-containing) SNc DA neurons extend their axons into the caudate putamen, where they synapse onto their immediate target cells, the striatal GABAergic medium spiny neurons (MSN) and cholinergic and GABAergic fast spiking (FS) interneurons (INs). The MSN neurons project to the internal or external segment of the globus pallidus which, in turn, are connected with the ventrolateral (VL) and ventroanterior (VA) thalamus or subthalamic nucleus in what is known as the direct or indirect pathway, respectively, of the basal ganglia (not depicted here). Retrograde degeneration of the axons and subsequently of the pigmented cell bodies in the SNc (right side) is one key histopathological feature of the PD brain. Created with BioRender.com.

Figure 2

The rodent mDA system in the adult brain. (A) Sagittal view (left) and enlarged midsagittal section (right) of the adult rodent (mouse, rat) brain, showing the location of the cell bodies (circles) from the A8 (RRF, pink), A9 (SNc, green), and A10 (VTA, blue) mDA clusters in the VM, and their projections (arrows) to the limbic areas (mesolimbic pathway), striatum (nigrostriatal pathway) and PFC (mesocortical pathway). Note that both the VTA and RRF DA neurons project to limbic areas in the mesolimbic pathway. The dotted and numbered lines indicate the position of the cross sections shown in (B,C). (B) Cross-sections of the rodent forebrain at the level of the dotted lines #1 and 2 in (A), depicting the location of the medial (mPFC, dark blue area) and lateral (lPFC, light blue area) PFC (#1) as one target area of the VTA DA subset, of the dorsolateral striatum (dlStr, green area), ventromedial striatum (vmStr, blue area), NAc shell or NAc core (pink area; right panel #2) as preferential target areas of the SNc, VTA and RRF DA subsets, respectively, and of the lateral septum (LS, yellow area) innervated by NEUROD6-and BCL11A-expressing mDA neurons. (C) Cross-sections at different rostro-caudal levels of the rodent midbrain, indicated by the dotted lines #3, 4 and 5 in (A), indicating the positions of the SNc (green lines), VTA (blue lines) and RRF (pink lines) DA subpopulations, as well as the location of the amygdala (AMG, pink area) as another target area in the mesolimbic pathway. Labeling of other brain regions in these sagittal and coronal views have been omitted for clarity. (D) Enlargement of the mDA region in the medial rodent VM [level of the dotted line and cross-section #4 in (A,C), respectively], showing the SNc (ventral tier, vSNc; dorsal tier, dSNc; medial tier, mSNc; and lateral tier, lSNc), VTA (PBP, parabrachial pigmented nucleus; PN, paranigral nucleus; IF, interfascicular nucleus; PIF, parainterfascicular nucleus; RLi, rostral linear nucleus; CLi, caudal linear nucleus of the raphe), and RRF subdivisions. Colored circles depict the approximate positions and proportions of mDA neurons with distinctive gene expression signatures (legend in bottom right corner) within these subdivisions, as summarized in this article. Colors and shadings indicate the increasing vulnerability (red triangle) of these mDA subsets to neurodegeneration. Intermediate shadings denote mDA subsets not defined here. Created with BioRender.com.

Figure 3

PD as a consequence of “multiple hits” or “stochastic acceleration” of an ongoing SNc DA neuron demise throughout the lifetime of a healthy organism. (A) Pre-and perinatal mDA neuron development (indicated by the transition from a proliferating mDA progenitor to a postmitotic mDA precursor to a maturing mDA neuron) endows a healthy human with an average number of 500,000 mDA neurons. Although still debated, a lifelong increased oxidative/nitrosative stress load coupled to a high proteostatic and energetic demand in particularly the SNc DA neurons lead to a continuous demise of some of these neurons (curved blue line) which, however, will not hit the crucial threshold (dashed horizontal black line indicating that only 50% of the mDA neurons remain in the human VM) during the usual human life expectancy. At this threshold, the first PD symptoms would appear (dashed vertical black line), and would worsen with increasing age (dashed pink line). (B) As suggested by the “multiple hit” or “stochastic acceleration” hypotheses, the normal mDA neuron demise (dashed blue line) is accelerated by the impact of diverse genetic and/or environmental stressors throughout the postnatal human lifetime (yellow flash and curved line), and will lead to the appearance of the first symptoms and diagnosis of PD (vertical black line) after reaching the critical threshold of mDA neuron numbers (dashed horizontal black line) in the sixth decade of life, as is the case in most (idiopathic) PD cases. Alternatively or in addition, a faulty pre-/perinatal mDA neuron development (orange flash) will render the individual with an already reduced number of mDA neurons at birth, which is still above the critical threshold and can thus be compensated by a heightened DA signaling and metabolism in the remaining mDA neurons from the human VM. Nevertheless, the normal age-related demise of these neurons, most likely together with additional postnatal impacts including a compromised mDA survival (dashed orange flash), will also lead to a much earlier surpassing of the critical threshold and diagnosis of PD (curved orange line). In both cases and due to the current lack of disease-modifying or-halting treatments, PD symptoms and thus severity of the disease will progressively worsen (pink line). The prodromal and presymptomatic period of life in these individuals (gray box) probably represents the best window of opportunity for the modification or, ideally, prevention of PD. Modified after (Le et al., 2009; Collier et al., 2011; Von Linstow et al., 2020).

Figure 4

Signaling pathways required for mDA neuron survival in the adult, aging or lesioned mammalian VM. Simplified schematic depiction of the FGF (brown), SHH (green), TGFb/BMP (pink) and WNT/b-catenin (blue) signaling pathways and TFs or transcriptional targets implicated in the adult survival and protection of mDA neurons. FGF, TGFb/BMP and WNT/b-catenin signaling take place in the mDA neurons themselves, whereas SHH signaling is not active in these neurons but in one of their striatal target cells [cholinergic (ACh) INs]. The simplified GDNF/RET/GFRa signaling complex (gray) has been added for clarity in this context. Small molecules frequently employed to activate or inhibit the corresponding pathway are also indicated. Arrows indicate activation, red crossbars indicate inhibition of the corresponding pathway or target gene/protein. Stippled lines label pathways or signaling components not yet demonstrated in adult mDA neurons. Question marks denote still unclear target genes, TFs or ligands for the corresponding pathway during mDA neuron maintenance. See text for details and abbreviations. Created with BioRender.com.