A new Perspective on Parkinson's disease: exploring the involvement of intestine and vagus lysates in α-synucleinopathy propagation

Synucleinopathies encompass a range of neurodegenerative disorders, including Parkinson's disease (PD) that is characterized by loss of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies /Lewy neurites in the central and peripheral nervous system^[2-4]. While PD is primarily recognized as a movement disorder, it is now understood that the symptoms extend beyond motor dysfunction, as individuals with PD frequently experience non-motor symptoms, particularly gastrointestinal dysfunction^[5]. There is a growing focus on the role of the GI tract and the enteric nervous system (ENS) in the onset and progression of PD^[6]. The ENS is a network of neurons located in the GI wall that plays a crucial role in the bidirectional communication system between the CNS and the GI tract, known as the gut-brain axis. According to the hypothesis proposed by Braak et al.^[7], α-syn pathology may have its origins in the ENS and propagates to the brain through autonomic nerves. In support of this notion, truncal vagotomy reduced the risk of PD in humans by 40%-50% after a follow-up period of 10-20 years^[8,9]. Additionally, the autonomic peripheral nervous system (PNS) has been found to deteriorate years before the nigrostriatal dopamine system in some PD patients^[10].

It is hypothesized that pathological α-syn species spreads in a prion-like manner from one cell to another through templated misfolding and/or aggregation of nascent or properly configured α-syn, which is then transmitted to adjacent cells^[11,12]. Studies support the transcellular spread of pathological α-syn through the demonstration that PD-like Lewy pathology can be induced in animals by injecting synthetic α-syn fibrils into different brain regions^[11,13], or by injecting pathological α-syn species^[14,15] from transgenic mice or patients with synucleinopathies into animal brains, leading to the propagation of α-syn pathology. Likewise, Yang et al.^[1] investigated the transmission of pathologic α-syn from a pathologically verified PD case to rats by injecting intestinal or vagus lysate directly into rat brains. Results showed that these lysates contained pathologic α-syn, which led to the formation of Lewy body-like inclusions in the substantia nigra (SN) and striatum (STR) of the recipient rats [Figure 1]. Additionally, the injection prompted the accumulation of α-syn aggregates across numerous brain regions, including the substantia nigra, striatum, brain stem, cortex (somatosensory and frontal), cerebellum, and hypothalamus, eventually resulting in the neurodegeneration of nigrostriatal dopaminergic neurons on both sides of the brain [Figure 1]. The findings of this study are largely in line with those of prior research, including Thomzig et al.'s demonstration that injecting homogenized brain and stomach wall samples from individuals with PD can trigger α-syn aggregation^[16]. Additionally, Recasens et al. found that injecting LB extracts from PD patients into the brains of wild-type mice and macaques caused the development of α-syn pathology and degeneration of the nigrostriatal system^[14]. Recent reports also observed α-syn aggregates in the ENS and vagus nerve. In rodent models, injecting pre-formed α-synuclein fibrils into sympathetic ganglia or duodenum muscle layers can cause α-syn deposition and propagation^[17-19]. In contrast, Prusiner et al. reported that the transmission of homogenates from brains affected by PD did not lead to the development of abnormal α-synuclein inclusions in transgenic mice, demonstrating the complex and heterogeneous nature of neurodegenerative diseases^[20]. In summary, while the results of the current study align with previous research, the intricate nature of neurodegenerative disorders highlights the need for continued investigation to gain a comprehensive understanding of the role of transmission of pathologic α-syn and its contributions to the progression of PD.

Figure 1. Experimental timeline and outcomes of rats that were injected with intestine lysate or vagus lysate obtained from an individual with PD, demonstrating the accumulation of human α-synuclein in the substantia nigra and other brain regions, activation of microglia and astrogliosis, loss of dopaminergic neurons, and propagation of pathological α-synuclein in bilateral brain regions.

Although the current study showed that pathologic α-syn species exist in the intestines and vagus nerve of a PD patient and that they can induce prion-like propagation of α-syn pathology in rats, they have some notable limitations. The study found that injecting lysates from a single PD patient's intestine and vagus induced α-syn pathology in rats, but this unilateral approach may not accurately reflect the bilateral nature of PD in humans. Similarly, the study also lacked lysates from non-PD individuals of the same age as controls and used lysates from only one PD patient, limiting the generalizability of the results. Therefore, these findings should be validated through further research with bigger sample sizes and additional replications. Another limitation of this research article is the lack of in vitro studies. In vitro models may have limitations in terms of physiological relevance compared to in vivo studies. However, they have been useful tools in investigating the mechanisms (exocytosis, axonal transport, tunneling nanotubes, endocytosis, and direct penetration) of intercellular transfer and seeding properties of pathologic α-syn. As such, the inclusion of in vitro studies in this research could have provided a more comprehensive understanding of the topic at hand. Further research that incorporates in vitro models may help to overcome this limitation and provide a more complete picture of the mechanisms underlying the initiation and spread of α-synucleinopathy in the brain. Finally, HPLC analysis was only performed on the intestine lysate group, not the vagus group. Notably, these limitations do not diminish the importance of the research, but further studies may be needed to provide a more complete picture of the disease.

The findings of this study hold potential importance for the field of PD research. The identification of the intestine and vagus as sources of pathologic α-syn that can propagate disease pathology is a novel finding that opens up new avenues of research. The study's findings on the prion-like propagation of α-syn aggregates in non-CNS tissues and their transmission to the brain have significant implications for future research in the field of PD. The future directions stemming from this study, such as investigating the nerve cell types that are vulnerable and the transmission mechanisms, as well as investigating potential safeguards to prevent the propagation of α-syn aggregates, have important implications for the development of effective therapies for PD. Overall, this study's novel findings and future directions provide a foundation for advancing our understanding of PD pathogenesis and developing new therapeutic strategies to enhance the quality of life for individuals with PD.