Environmental Parkinson's Disease Research Articles

The nigro-vagal modulation of the proximal colon is compromised in a model of environmental Parkinson's Disease

Parkinson’s Disease (PD) is a prevalent neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which results in tremor, rigidity and bradykinesia. Up to 80% of the PD patients suffer from constipation about 10 to 20 years before experiencing motor symptoms. We previously reported that a monosynaptic pathway connects SNpc to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric and proximal colon motility, and gastric motility is impaired in an environmental model of parkinsonism, induced by oral administration of subthreshold doses of paraquat (P) and lectin (L) (PMID 30302391). The current study was designed to test the hypothesis that nigro-vagal modulation of the proximal colon is compromised in the oral P+L model of parkinsonism.Proximal colonic motility and tone were recorded in age-matched male rats via a strain gauge aligned with the colonic circular smooth muscle, approximately 3 cm distal to the ileal-cecal valve. Activation of SNpc neurons via microinjection of the ionotropic glutamate selective agonist, NMDA, increased proximal colonic motility (187±52.6% of baseline, n=13; Paired t test, p<0.0001) and tone (323±97.2mg, n=14). In our rat model of environmental parkinsonism, baseline colonic motility (155.2±49.6mg, n=5) showed no change compared to control rats (146.6±67.8mg, n=5; Unpaired t test, p=0.0387), however, the ability of NMDA-induced SNpc activation to increase colonic tone and motility was decreased (tone 303.4±70.8mg, n=5 vs 500.8±207.5mg in control rats, n=5; unpaired t test, p=0.0395; motility 139.8±24.8% of baseline, n=4 vs 222.6±62.9% of baseline of the age matched control rats, n=3; unpaired t test, p=0.0439). Gastro-cecal transit, measured using the 13C lactose ureide-breath test, showed that transit time was increased in parkinsonian rats from 132.7±28 min (n=7) to 218.4±59.4 min (n=11; one-way ANOVA, p=0.0026). Chemogenetic inhibition of the nigro-vagal pathway attenuated the delay in transit in parkinsonian rats to 173.2±16.3 min (n=5; one-way ANOVA, p=0.2886 vs control rats).These data suggest that intestinal transit is delayed, and the ability of the SNpc to modulate proximal colon motility and tone is attenuated in a model of environmental parkinsonism. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed both in patients and in animal models of Parkinson Disease. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Meta-analysis of genetic and environmental Parkinson's disease models reveals a common role of mitochondrial protection pathways

Both genetic and environmental factors trigger risks of and protection from Parkinson's disease, the second most common neurodegenerative syndrome, but possible inter-relationships between these risk and protection processes were not yet explored. By examining gene expression changes in the brains of mice under multiple treatments that increase or attenuate PD symptoms we detected underlying disease and protection-associated genes and pathways.In search for potential links between these different genes and pathways, we conducted meta-analysis on 131 brain region transcriptomes from mice over-expressing native or mutated α-synuclein (SNCA) with or without the protective HSP70 chaperone, or exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. All these models showed shared risk-inducible and protection-suppressible transcript modifications. Self-organized map (SOM) classification revealed risk- and protection-associated alterations in nuclear and mitochondrial metal ion-regulated transcripts, respectively; Gene Ontology based analysis validated these pathways. To complement this approach, and identify potential outcome damages, we further searched for shared functional enrichments in the lists of genes detected in young SNCA mutant or in old SNCA mutants and MPTP-exposed mice. This post-hoc functional analysis identified early-onset changes in Parkinsonian, immune and alternative splicing pathways which shifted into late-onset or exposure-associated NFkB-mediated neuro-inflammation. Our study suggests metal ions-mediated cross-talk between nuclear and mitochondrial pathways by both environmental and genetic risk and protective factors involved in Parkinson's disease, which eventually culminates in neuro-inflammation. Together, these findings offer new insights and novel targets for therapeutic interference with the gene–environment interactions underlying sporadic PD.