Does Parkinson's disease start in the gut?

Abstract

In 1997, two major discoveries contributed to the understanding of the pathogenesis of Parkinson's disease (PD). Firstly, the identification of mutations in the alpha-synuclein gene (SNCA) as being responsible for hereditary forms of PD 1 and, secondly, the finding that aggregated, misfolded alphasynuclein (ASN) was one of the major components of Lewy bodies and Lewy neurites 2 , the hallmark lesions of sporadic forms of the disease. Other monogenic forms of the disease (LRRK2, and SNCA duplications and triplications) also have ASN deposits as a distinguishing pathological feature 3 . Other parkinsonian syndromes (multiple system atrophy and dementia with Lewy bodies) were found to be part of a spectrum of disorders, sharing the accumulation of misfolded ASN at the neuronal and glial level, giving birth to the concept of synucleinopathies: neurodegenerative diseases whose pathological marker is the presence of these deposits of abnormally conformed ASN ; pathologic accumulation of ASN is toxic and can interfere with normal synaptic function, dopamine transport, and protein degradation 8 . Moreover, a widespread distribution of ASN pathology, at both the central and peripheral levels, reflects the expression of symptoms of PD, establishing that the disease is a multisystem disorder with both motor and non-motor symptomatology 9 . Another pivotal contribution to our understanding of the pathogenesis of PD has been the comprehensive and detailed description by Braak et al. 10 of the spreading of ASN pathology in the brain of affected individuals. According to their findings, these authors established a pattern of disease progression that correlated with brain ASN pathology in which the course of the disease evolved in stages (I through VI) of increasing involvement. In stages I and II, the areas of ABSTRACTCurrent understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies.Keywords: Parkinson's disease; enteric nervous system; alpha-synuclein. RESUMOO atual entendimento sobre a fisiopatologia da doença de Parkinson (DP) sugere um papel central do acúmulo de alfa-sinucleína na patogenia da DP. Esta revisão crítica revisita marcos, teorias e controvérsias a respeito da origem e progressão da sinucleinopatia, apresentando uma atualização das principais evidências sugerindo que o sistema nervoso entérico seria o local inicial deste processo. Apesar das evidências a favor desta teoria serem crescentes e instigantes, as lacunas de conhecimento a este respeito são importantes pontos para estudos futuros.Palavras-chave: doença de Pa...

Avaliação do impacto de sintomas psiquiátricos na qualidade de vida em pacientes com doença de parkinson

“…Na verdade, uma vez que a constipação pode preceder em até 10 anos o aparecimento dos sintomas motores, recentemente foi descrita uma teoria de que a DP tem origem no Sistema Nervoso Entérico (SNE), composto pelos plexos mioentérico e submucoso. De acordo com essa teoria, um patógeno capaz de ultrapassar a mucosa gastrointestinal poderia induzir a produção anormal de alfa-sinucleínas nos axônios terminais de neurônios entéricos pós-ganglionares e esse evento seria seguido de transporte retrógrado para neurônios pré-ganglionares colinérgicos do NMDV e, a partir daí, haveria o espalhamento para outras áreas cerebrais (GERSHANIK, 2018).…”

One Step Into the Future: New iPSC Tools to Advance Research in Parkinson’s Disease and Neurological Disorders

“…One of the major advantages to combining iPSC-derived tissue and microfluidic chips is the possibility of deriving multiple organs from the same donor or patient. As mentioned above, connection of gut and brain organoids from a PD patient would be an interesting chip to develop, to investigate the impact of microbiota on the development of pathological markers, such as α -synuclein, which is suspected to spread from the enteric nervous system to the brain via the vagus nerve [142]. “Gut-on-a chip” systems have already been developed to test the inflammatory impact of microbial infection on intestinal epithelial cells [143].…”

Fecal Microbiota Transplants as a Treatment Option for Parkinson’s Disease

“…Since PD is assumed to be characterized by synucleinopathy, another potential mechanism may be that alpha-synuclein produced by gut microbiota spreads upwards from the gut along vagal nerve fibers [34,35].…”