Neuropathology Theories Of Parkinson’S Disease
The two key pathological hallmarks of PD are the Lewy bodies (LB) and the progressive loss of dopaminergic neurons in the SNpc, although increasing evidence supports that other areas and nuclei of the nervous system are affected as well. Parkinson’s disease and dopamine depletion Although toxic accumulation of αsyn oligomers is assumed to be the most contributing factor to the pathogenesis of PD, motor symptoms are still the basis for clinical diagnosis (O’Keeffe and Sullivan, 2018). Motor impairment is caused by the decrease in striatal DA levels due to the loss of the projecting dopaminergic neurons of the SNpc. “Why are the DA neurons lost in PD?” may be one of the most formulated questions in this field. To answer this, two hypotheses (which are compatible with each other) have been widely recognized. One of them considers mitochondrial dysfunction (and thus oxidant stress) as the main culprit of DA neuronal death (Haelterman et al. , 2014). The other theory holds that DA neurons are more susceptible to αsyn oligomers’ toxicity, as they have been found in different brain areas at early stages of the disease without causing neurodegeneration or cell death (Osterberg et al. , 2015; Brundin and Melki, 2017a).
Several evidence points out that the selective vulnerability of these neurons to both mitochondrial dysfunction and αsyn toxicity relies on several features of the SNpc DA neurons: they possess long unmyelinated axons with large number of neurotransmitter release sites (Poewe et al. , 2017; Surmeier et al. , 2017), cytosolic calcium regulation is energy-dependent (Surmeier et al. , 2017), and dopamine metabolism is associated with oxidative stress (Surmeier et al. , 2017; Surmeier, 2018). For an excellent review see Ref (Surmeier et al. , 2017). It is clear that dopaminergic cell death in the SNpc is a key element for motor deficits. However, accumulating evidence suggest that, in the dopaminergic system, the neurodegenerative process starts in the nigrostriatal terminals of the midbrain neurons at early stages of the disease, as some studies have shown that there is a greater reduction of the dopaminergic markers as the aromatic L-amino-acid decarboxylase (AADC), the dopamine transporter (DAT), the activity of vesicular monoamine transporter type 2 (VMAT2) or tyrosine hydroxylase (TH) immunoreactivity in the striatum than in the SNpc at different disease stages (Matsuda et al. , 2009; Caminiti et al. , 2017). These results are supported by neuroimaging studies that have also found that the reduction of dopaminergic signals is greater in the putamen than in the SN (Hsiao et al. , 2014; Kaasinen and Vahlberg, 2017). These results have a wide list of implications, that ranges from early diagnosis to therapies focused on axonal regeneration from residual DA neurons (O’Keeffe and Sullivan, 2018). Lewy bodies Protein inclusions are key players in many neurodegenerative disorders, like PD, Alzheimer’s disease and some type of dementia (Kalia and Kalia, 2015).
One of the most studied protein aggregates are the Lewy bodies, named in honour to its discoverer Fritz Heinrich Lewy who found them in brains of PD patients (Goedert et al. , 2013a; Kalia and Kalia, 2015). The LB were are fibrillary inclusions that can be found in cell bodies and neurites and since they were described in 1912, almost 100 molecules have been discovered as LB components, including alpha-synuclein (αsyn), LRRK2, PINK-1, parkin and DJ-1 (Wakabayashi et al. , 2012; Toulorge et al. , 2016). For a detailed review of LB composition see Wakabayashi et al. , 2012. The most contributing component is the presynaptic protein αsyn, both in sporadic PD and hereditary PD. The main physiological functions of αsyn are neuronal membrane stabilization, regulation of vesicular transport and pre-synaptic signalling (Lashuel et al. , 2002b; Brundin and Melki, 2017b), and this protein is not found in the neuronal cytoplasm (Wakabayashi et al. , 2012). Point mutations in the αsyn gene (SNCA) together with environmental factors provoke changes in its synthesis, maturation and post-translational processing, finally promoting the protein oligomerization to a toxic form (Wakabayashi et al. , 2012; Osterberg et al. , 2015; Brundin and Melki, 2017a). In PD and dementia with Lewy bodies, these inclusions are found in cell bodies and in the processes of neurons and glial cells, presented as two morphologically distinct entities: Lewy bodies and Lewy neurites (Malek et al. , 2014; Osterberg et al. , 2015). LB have also been found in peripheral tissues of PD patients (Malek et al. , 2014; Brundin and Melki, 2017a; Htike et al. , 2018), giving the opportunity to use it as an early maker (allowing to early detect the disease with the possibility to treat the patient and try to establish disease-modifying treatments. A large piece of evidence has demonstrated the direct pathogenic role of αsyn in PD, other Lewy body pathologies and lysosomal disorders, both by genetic and histopathological studies (Wakabayashi et al. , 2012).
A broad spectrum of pathogenic mechanisms of the αsyn aggregates have been proposed, among them: i) impairment of the normal organelle´s function, giving rise to a vicious cycle of toxicity (Lang and Espay, 2018; Surmeier, 2018); ii) dopamine interaction, making DA neurons more susceptible (Surmeier et al. , 2017; Surmeier, 2018); iii) activation of inflammatory processes (Ferreira and Romero-Ramos, 2018); iv) its ability to act as a prion-like protein, transmitting from one cell to another (Osterberg et al. , 2015; Brundin and Melki, 2017a). Contrary to what has been assumed, some authors have placed αsyn aggregation as a neuroprotective mechanism in PD (Ding et al. , 2002; Lashuel et al. , 2002b; a). PD evolution: Braak’s theory Since the discovery of LB, it has been very well established that these proteinaceous inclusions not only affect the population of neurons in the SNpc. The studies conducted by Braak and colleagues in 2003 found that actually, the SNpc was not the first structure where PD-related lesions could be found (Braak et al. , 2003). The presence of lesions in other brain areas in the early stages of the disease as the olfactory bulb or the gut myenteric plexus (prior neurodegeneration of the nigrostriatal pathway and motor symptoms appear), could explain the development of non-motor symptoms, as smell impairment, sleep alterations, constipation or depression (Braak et al. , 2003; Braak and Del Tredici, 2017).
According to their results, they postulated a six-stage theory for the development of Lewy’s pathology in sporadic PD (Braak et al. , 2003). This theory considers that Lewy deposits sequentially invade neuroanatomically interconnected pathways until they reach the neurons of the SNpc and LC (Figure 1A) (Braak et al. , 2003). The first affected structures would be non-dopaminergic areas with vulnerable environmental cellular conditions, such as the olfactory bulb or the enteric nervous system (ENS) (Braak et al. , 2003; Brundin and Melki, 2017a). The areas affected in the first stages (stage 1 and 2) include the olfactory bulb, the dorsal nucleus of the vagal nerve, locus coeruleus and caudal raphe nuclei. Then, the LB lesions extend to the amygdala, the pedunculopontine nuclei, and the SNpc (stages 3 and 4). Finally, in stages 5 and 6 there is a severe extent of the brain affected, including neocortical areas, temporal lobe and limbic structures as the hippocampal formation or the anteromedial temporal mesocortex, which directly correlate with cognitive impairment (Braak et al. , 2003). The way that aggregates of misfolded αsyn go from the initially affected regions to the SNpc is still unclear and many hypotheses have been proposed (for more information see reference Braak and Del Tredici, 2017).
However, the repercussions of this staging theory are notable. On the one hand, it allows the study of the disease in the peripheral nervous system (PNS), ENS and spinal cord, and the possibility to establish diagnostic markers and risk factors (Braak and Del Tredici, 2017). On the other hand, including this perspective in experimental studies of the disease will provide a wide range of information in order to better understand the development and evolution of the disease (Brundin and Melki, 2017a). Additionally, strategies for therapy may emerge before the nigrostriatal pathway is affected (Braak and Del Tredici, 2017; Aaseth et al. , 2018).
