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How would defining Parkinson’s as a prion disease impact the search of a cure?

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of aberrant aggregates of α-synuclein, resulting in a clinical syndrome defined by motor and non-motor manifestations. Alpha-synuclein inclusions are known as Lewy-bodies (LBs) and Lewy neurites (LNs), whether they accumulate in neuronal perikarya or in neuronal processes, respectively [1]. Braak seminal studies on the pattern of distribution of pathological α-synuclein in PD postmortem human brains suggested a stereotypical and disease-course related accumulation of α-synuclein in different areas of the central and also the enteric and autonomous nervous system [2]. In 2008, two independent research teams identified classical α-synuclein pathology in the embryonic neurons which had been transplanted into the brains of PD patients as a potential stem cell treatment [3,4]. In the next year, those findings were provided a possible explanation with the evidence that α-synuclein aggregation demonstrates a capability of transmitting from neurons to neural stem cells in vitro and in vivo [5]. In light of all these findings, it was suggested that α-synuclein could behave like a prion, being able to recruit its endogenous physiological counterpart and template onto it its aberrant conformation, leading, ultimately, to neurodegeneration [6] (Figure 1). This hypothesis was subsequently supported by several studies performed using in vitro produced recombinant α-synuclein aggregates, which efficiently induced pathology both in vitro and in vivo [7,8]. Notably, despite aggregated α-synuclein shares some features with prions, to date prion diseases are the only neurodegenerative disorders showing infectious transmissible protein species capable of recapitulating clinical disease [9,10]. No clear evidence exists to naturally occurring human-to-human transmission of other neurodegenerative conditions [11,12]. Similar to prions, α-synuclein aggregates may present in different conformers (i.e. strains) [13,14] with relevant pathological and clinical implications [15]. The prion hypothesis for α-synuclein also accounts for Braak observations, which suggest that α-synuclein accumulation could begin either in the olfactory bulb or in the gastrointestinal tract and subsequently spread to the ventral midbrain, where it selectively affects dopamine neurons of the substantia nigra pars compacta (SNpc). According to the ‘dual hit’ hypothesis, proposed to explain PD pathological progression, an unknown pathogenic assault could reach the brain through two routes: the nose and the gut [16]. These two compartments are, indeed, both in close and constant contact with the external environment, and so, with potential detrimental effectors. If the pathological process starts in the olfactory mucosa (OM) it can reach the brain directly through the olfactory system or retrogradely, via the enteric plexus and then the vagal nerve. In fact, affected olfactory cells containing α-synuclein aggregates can detach from OM and be subsequently swallowed within saliva and mucus reaching the stomach and then the enteric plexus (Figure 1). Accordingly, clinical signs of an early involvement of gut and olfactory compartments, such as hyposmia and gastrointestinal dysfunction (e.g. reduced bowel movements) are frequently reported in PD early phases [16]. This gut to brain spread has been recently reproduced in vivo with α-synuclein in vitro preformed fibrils (PFF) injected in the stomach and duodenum of wild-type mice [17]. Interestingly, the absence of endogenous α-synuclein and truncal vagotomy completely prevented this spreading in the injected animals.