Comprehensive Review on Potential Signaling Pathways Involving the Transfer of α-Synuclein from the Gut to the Brain That Leads to Parkinson’s Disease

Abstract

Parkinson’s disease is the second most prevalent neurological disease after Alzheimer’s. Primarily, old age males are more affected than females. The aggregates of oligomeric forms of α-synuclein cause the loss of dopaminergic neurons in the substantia nigra pars compacta. Further, it leads to dopamine shortage in the striatum region. According to recent preclinical studies, environmental factors like pesticides, food supplements, pathogens, etc. enter the body through the mouth or nose and ultimately reach the gut. Further, these factors get accumulated in enteric nervous system which leads to misfolding of α-synuclein gene, and aggregation of this gene results in Lewy pathology in the gut and reaches to the brain through the vagus nerve. This evidence showed a strong bidirectional connection between the gut and the brain, which leads to gastrointestinal problems in Parkinson patients. Moreover, several studies reveal that patients with Parkinson experience more gastrointestinal issues in the early stages of the disease, such as constipation, increased motility, gut inflammation, etc. This review article focuses on the transmission of α-synuclein and the mechanisms involved in the link between the gut and the brain in Parkinson’s disease. Also, this review explores the various pathways involved in Parkinson and current therapeutic approaches for the improvement of Parkinson’s disease.

Modulation of Neurotransmitter Pathways and Associated Metabolites by Systemic Silencing of Gut Genes in C. elegans

“…Considering the roles of alpha-synucleine aggregation and dopamine decline in PD [38], we studied these 48 genes in reference to alteration in transgenic expression of human α-Synuclein and behavioural assays that are governed by the dopamine-signalling pathway, to perform a screening of those genes that affect these parameters. Different studies have demonstrated that α-Synuclein aggregation might change the metabolite profiling in the gut [39]. A study conducted on monkeys showed significantly elevated levels of L-aspartic acid, p-hydroxyphenylacetic acid, and glyceric acid, hence our idea here was to see whether alteration in levels of these genes can affect the parameters of neurodegeneration or neuronal health.…”

Amelioration of olfactory dysfunction in a mouse model of Parkinson’s disease via enhancing GABAergic signaling

“…Growing evidence suggests that there are distinct olfactory and gastrointestinal pathologies in the early stage of PD, which can significantly impact social functioning [ 2 , 3 , 48 – 50 ]. However, early treatments for these pathologies in PD are rare.…”

Biomarkers for Managing Neurodegenerative Diseases

“…Lewy bodies, comprised of aggregated pathological α-synuclein, are the histological hallmark of PD pathology, and have been demonstrated to trigger a chain of misfolding in healthy proteins, migrate from cell to cell in a prion-like fashion, and promote neu-rodegeneration and neuroinflammation [83,84]. There are multiple potential sites of initial pathological protein aggregation; the landmark Braak hypothesis posits that α-synuclein misfolding begins in the gut, migrates up the vagus nerve to the olfactory bulb, and spreads throughout DA neural circuitry to reach DA neurons in the SNpc [83,85]. In support of this theory, Lewy bodies have been identified in presymptomatic PD-patient intestine, and PD patients frequently report GI symptoms and anosmia decades prior to developing motor deficits [81,82,86].…”