The protein α-synuclein can misfold in ways that encourage other α-synuclein molecules to also misfold in the same way. These misfolded proteins spread slowly from cell to cell through the nervous system, clumping together to form aggregates surrounded by a toxic biochemistry that stresses and kills neurons. This gives rise to the age-related neurodegenerative conditions known as synucleinopathies, characterized by the formation of Lewy bodies, aggregates of α-synuclein that form inside neurons. Parkinson's disease is the synucleinopathy that receives the most attention; motor neurons are the most vulnerable to disease pathology, and motor function is affected as these vital cells die, giving rise to the most evident symptoms of the condition.
An association between gastrointestinal dysfunction and Parkinson's disease was noted long before the advent of modern biotechnology. Now, given the means to study the biochemistry and microbial populations of the gastrointestinal tract in fine detail, researchers have found that in many cases misfolded α-synuclein appears to originate in the intestines and then spread to the brain. Associations exist between specific differences in the gut microbiome and Parkinson's disease. It remains to be seen as to what will emerge from all of this work; the best way forward may be to develop efficient ways to clear misfolded α-synuclein, and in that case the mechanisms of origin and spread will become irrelevant.
Lewy body diseases and the gut
Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies.
Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs.
We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.
View the full article at FightAging
