Figure 1.

Scheme of the unifying hypothesis of dopamine neuron loss in neurodegenerative diseases. (A) Scheme of the dopaminergic projections arising from the VTA, SNpc, and LC. The dopaminergic neurons of the SNpc project mainly to the dorsal striatum (caudate and putamen), mediating the control of voluntary movements via the direct and indirect pathways (Calabresi et al., 2014). Degeneration of these neurons is the main cause of motor symptoms in PD (Surmeier, 2007). LC TH⁺ neurons innervate most of the cortex and subcortical regions and have been shown to be important for cognitive and non-cognitive functions, memory consolidation, attention, sleep-wake cycle, mood, and emotional processing (Palmer et al., 1987; Sara, 2009; Robertson et al., 2013; Kempadoo et al., 2016; Roy et al., 2016; Takeuchi et al., 2016; Borodovitsyna et al., 2017). The VTA is the origin of TH⁺ axons forming the mesocortical and the mesolimbic dopaminergic pathways, together called the mesocorticolimbic system (Gasbarri et al., 1994; Björklund and Dunnett, 2007). The mesocorticolimbic system projects primarily to the prefrontal cortex, hippocampus, NAc, olfactory bulb, amygdala, and anterior cingulate cortex. This system is implicated in motivated behaviors, reward and emotional processing, memory, and learning. Loss of VTA and LC TH⁺ neurons in AD is thought to be the basis for memory deficits, cognitive, and neuropsychiatric symptoms (Kelly et al., 2017; Nobili et al., 2017; D'Amelio et al., 2018a; Serra et al., 2018), while loss of VTA and LC TH⁺ neurons in PD is linked to the appearance of neuropsychiatric symptoms and dementia (Jellinger, 1991; German et al., 1992; Surmeier, 2007; Costa et al., 2012; Alberico et al., 2015; Caminiti et al., 2017). (B) Scheme of TH⁺ cell death in age-related neurodegeneration. Several factors (such as genetic background, genetic mutations, age, environmental or lifestyle risk factors), either alone or in combinations, might selectively dispose TH⁺ neurons of a specific area (SNpc, VTA, LC) to degenerate. Moreover, these neurons are more prone than others to cell death due to features that make them particularly sensitive: these cells are long-projecting neurons with poorly or completely unmyelinated axons that provide massive synaptic innervations in projecting areas (Braak et al., 2006), they have autonomous pacemaker activity due to which they have high requirements for energy and therefore also require efficient mitochondrial function. From a clinical point of view, the manifestation of clinical symptoms is strictly associated with the functions of SNpc-, VTA-, and/or LC-projecting areas.