Alpha-Synuclein Pathology and the Role of the Microbiota in Parkinson’s Disease

Abstract

There is a principle in science, known as Occam’s razor, that says the correct solution is usually the one with the simplest explanation. The microbiota-gut-brain axis, an interdependent series of communication loops between the enteric nervous system (ENS), the microbiota, the gut, and the brain, offers important insight into how changes in our gut affect distant organs like our brains. The inherent complexity of this axis with the crosstalk between the immune system, inflammatory states, and the thousands of bacteria, viral, and fungal species that together make up the microbiota make studying the interactions that govern this axis difficult and far from parsimonious. It is becoming increasingly clear that the microbiota is integral to this axis. Disruption of the healthy flora, a phenomenon collectively referred to as dysbiosis, has been implicated as a driver for several diseases such as irritable bowel syndrome, rheumatoid arthritis, obesity, diabetes, liver disease, and neurological disorders such as depression, anxiety, and Parkinson’s disease (PD). Teasing apart these complex interactions as they pertain to PD is critical for our understanding of this debilitating disease, but more importantly, for the development of future treatments. So far, treatments have been unable to stop this neurodegenerative disease, succeeding only in briefly dampening symptoms and buying patients time before the inevitable loss of function ensues. Given that the 10 years prognosis for death or life-limiting disability with someone diagnosed with PD is upwards of 80%, there is a desperate need for curative treatments that go beyond symptom management. If PD does begin in the periphery with bidirectional communication between the microbiota and the immune system, as recent literature suggests, there is an exciting possibility that progression could be stopped before it reaches the brain. This systematic review assesses the current literature surrounding the role of the microbiota in the pathogenesis of alpha-synucleinopathies and explores the hypothesis that alpha-synuclein folding is modulated by the microbiota. Furthermore, we discuss how changes in the gut environment can lead to pathology and outline the implications that advances in understanding the interactions between host and microbiota will have on future research and the development of potential biomarkers.

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

“…As c-Rel is a crucial determinant of Treg identity and function (Grinberg-Bleyer et al, 2017), it may be easily conceivable that compromised Treg-mediated activity make c-Rel-deficient mice more vulnerable to microbiota-dependent bowel inflammation. The enteric inflammatory microenvironment, together with LPS, present at the outer membrane of Gram-negative bacteria, would, in turn, promote α-syn conformational shifts, aggregation, and spreading (Kim C. et al, 2016;Fitzgerald et al, 2019). Our observations, showing that young c-Rel ko mice exhibit α-syn accumulation in the distal colon (Parrella et al, 2019) anticipating the progressive α-syn brain deposition, sound in line with this hypothesis.…”

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…Nair et al, 2018 (iv) The vagal nerve, which serves as channel for α-syn from the ENS to the CNS, is crucial for the communication between gut microbiota and the brain. Ulusoy et al, 2013;Scheperjans et al, 2015;Fitzgerald et al, 2019 (v) Pathological hallmarks of PD are a loss of dopaminergic neurons in the SN and the presence of cytoplasmic eosinophilic inclusions termed Lewy bodies (LBs). Lebouvier et al, 2009 (vi) Immunolabeling with α-syn antibodies have become the reference standard in the assessment of LBs and Lewy neurites in both the CNS and peripheral nervous system.…”

Is Alzheimer’s Disease a Liver Disease of the Brain?

“…Alzheimer's disease (AD), the most common form of dementia, is a case in point. In the second most common neurodegenerative disorder, Parkinson's disease, new research is suggesting a role for the microbiota-gutbrain axis in alpha-synuclein pathology in the brain (reviewed in [1]).…”