The intricate debate on neurodegeneration and neuroinflammation in Parkinson’s disease: which came first?

Abstract

Parkinson’s disease (PD) is a heterogeneous multifactorial disorder and, during the last years, new scientific evidence has supported this concept. The principal hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta and the aggregation of misfolded alpha-synuclein (α-syn). In particular, α-syn is receiving great attention for its key role in PD neuropathology. Both genetic mutations and post-translational modifications (i.e., α-syn phosphorylation) can induce protein misfolding. An abnormal accumulation of this misfolded α-syn crushes both the ubiquitin-proteosome and autophagy systems, which are involved in protein clearance. As a result, α-syn aggregation leads to neuronal dysfunction and neurodegeneration. Along with this pathological condition, dysregulated mitochondrial activity, reactive oxygen species production, oxidative stress, and blood-brain barrier alteration, are typical features of neurological disorders such as PD. In addition, neuroinflammatory processes are critical for PD pathogenesis and strictly interconnected to α-syn pathology. According to this, neuroinflammation could be considered as a potential early drug target. The primary hallmark of PD is α-syn, one of the main components of Lewy bodies. Cardinale et al. (2021) have shown how mapping the journey of α-syn and its region-dependent effects is one of the stumbling blocks that researchers have encountered over the years to explain if neurodegeneration is closely intertwined with α-syn misfolded forms. The spreading of misfolded α-syn through the brain depends on disease progression (Braak et al., 2003). α-syn is highly expressed in the substantia nigra pars compacta and other regions affected by PD (Calabresi et al., 2014). In the normal brain of a rhesus monkey, α-syn is largely distributed in the whole brain; in particular, the substantia nigra, the hippocampus, and the neocortex express high α-syn levels and they are also notably vulnerable during the progression of idiopathic PD (Yang et al., 2021). The topic concerning the role of the different species of α-syn also seems to be rather controversial. The toxicity of α-syn is associated with its oligomeric and protofibrillar forms (Bras et al., 2020). On the other hand, there is controversial evidence of the physiological α-syn monomer role in the presynaptic vesicle formation mediated by soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex and neurotransmission (Calo et al., 2021). The molecular mechanisms underlying how α-syn oligomers drive the death of neurons remain unclear. Yoo et al. (2021) recently proposed an interesting and original question: can the physiological function of monomers and the toxicity of oligomers influence synaptic transmission in a correlative way? As other studies report, both monomers and oligomers to combine inhibit SNARE-mediated vesicle fusion. Yoo et al. (2021) have shown that the low concentration of oligomers, together with abundant monomers at the presynaptic terminals, can inhibit vesicle fusion efficiently. This ambitious work sets new prospects no longer directed to the singular study of a specific form of pathological α-syn. Therefore, it seems necessary not to exclude any factor to investigate what may occur during their interactions, in order to understand the pathology generated by α-syn oligomers and to develop improved therapeutic strategies. Regarding the protofibrillar form of α-syn, in the last ten years, several experimental studies have increasingly enhanced understanding of the role of this form in synaptic transmission and plasticity. A recent study by Tozzi et al. (2021) identified two early time points, at 6 weeks and 12 weeks after protofibril α-syn intrastriatal injection in adult male Wistar rats, to clarify how α-syn induces alterations in distinct forms of corticostriatal plasticity. The authors found that the spontaneous firing rate was absent in the cells recorded at 6 weeks post-injection, long-term potentiation was blocked, together with a reduction of dopamine release in striatum. On the contrary, at 12 weeks post-injection, dopaminergic neurons showed an increased firing rate, an impaired long-term depression, and a decrease of dopamine release compared to sham-operated rats, when a marked death of TH+ cells arose. From this latest study, it can be inferred that the specific mechanism of neurotoxicity induced by α-syn at different time points remains an open field of exploration. Neuroinflammation is strictly associated with α-syn pathology and neuronal degeneration in PD. As mentioned previously, we described the mechanism by which α-syn alters neuronal functions in PD and how this causes inflammation signs (Cardinale et al., 2021). Which came first, the chicken or the egg? We could extend this ancient paradox to PD. Which came first, neuroinflammation or dopaminergic cell death? Over many years, the long debate on neuroinflammation an