Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple ...biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.
The pathogenesis of Parkinson's disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many ...diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD.
Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS).
The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies.
Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts.
Iron is an essential nutrient for mitochondrial metabolic processes, including mitochondrial respiration. Ferritin complexes store excess iron and protect cells from iron toxicity. Therefore, iron ...stored in the ferritin complex might be utilized under iron-depleted conditions. In this study, we show that the inhibition of lysosome-dependent protein degradation by bafilomycin A1 and the knockdown of NCOA4, an autophagic receptor for ferritin, reduced mitochondrial respiration, respiratory chain complex assembly, and membrane potential under iron-sufficient conditions. However, autophagy did not contribute to degradation of the ferritin complex under iron-sufficient conditions. Knockout of the ferritin light chain, a subunit of the ferritin complex, inhibited ferritin degradation by decreasing interactions with NCOA4. However, ferritin light chain knockout did not affect mitochondrial functions under iron-sufficient conditions, and ferritin light chain knockout cells showed a rapid reduction of mitochondrial functions compared with wild-type cells under iron-depleted conditions. These results indicate that the constitutive degradation of the ferritin complex contributes to the maintenance of mitochondrial functions.
1-Methyl-4-phenylpyridinium (MPP+)-treated human neuroblastoma SH-SY5Y cells have been generally accepted as a cellular model for Parkinson's disease. To understand comprehensive metabolic ...disturbances in this model, both cell lysates and culture supernatants were subjected to metabolomic analysis. As expected from the fact that MPP+ inhibits mitochondrial complex I, a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis was indicated by an increase in extracellular lactic acid and a parallel depletion of pyruvic acid. In cell lysates, the metabolic shift was supported by consistent decreases in TCA cycle intermediates. Metabolomic analysis also revealed aberrant choline metabolism. Choline in the culture supernatant was elevated 8.5- and 17-fold by 30 and 300 μM MPP+ exposure, respectively; therefore, extracellular choline might be a metabolic biomarker for Parkinson's disease.
•Metabolomic analysis of cell lysates but culture supernatants was performed.•MPP+ caused a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis.•MPP+ induced aberrant choline metabolism.•Extracellular choline level might be a metabolic biomarker for Parkinson's disease.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has ...revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo ...process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62. The number and size of these inclusions were gradually increased in neurites rather than soma with aging. These inclusions may facilitate peripheral failures. As a result, DA neuron loss and motor dysfunction including the hindlimb defect were observed in 120-week-old mice. P62 aggregates derived from an autophagic defect might serve as "seeds" and can potentially be cause of LB formation.
Summary Background Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with ...autosomal dominant Parkinson's disease to identify novel causative genes. Methods We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles. Findings We identified a missense mutation ( CHCHD2 , 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (−9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48–4·24; p=0·0004) and 4·69 (1·59–13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96–1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping. Interpretation CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease. Funding Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.
Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and the deposition of specific protein aggregates of α-synuclein, termed Lewy bodies, is evident in ...multiple brain regions of PD patients. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with the pathogenesis of PD. Here we found that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in the mouse striatum was attenuated by subsequent repeated administration of TPPU, a potent sEH inhibitor. Furthermore, deletion of the sEH gene protected against MPTP-induced neurotoxicity, while overexpression of sEH in the striatum significantly enhanced MPTP-induced neurotoxicity. Moreover, the expression of the sEH protein in the striatum from MPTP-treated mice or postmortem brain samples from patients with dementia of Lewy bodies (DLB) was significantly higher compared with control groups. Interestingly, there was a positive correlation between sEH expression and phosphorylation of α-synuclein in the striatum. Oxylipin analysis showed decreased levels of 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid in the striatum of MPTP-treated mice, suggesting increased activity of sEH in this region. Interestingly, the expression of sEH mRNA in human PARK2 iPSC-derived neurons was higher than that of healthy control. Treatment with TPPU protected against apoptosis in human PARK2 iPSC-derived dopaminergic neurons. These findings suggest that increased activity of sEH in the striatum plays a key role in the pathogenesis of neurodegenerative disorders such as PD and DLB. Therefore, sEH may represent a promising therapeutic target for α-synuclein–related neurodegenerative disorders.
Background
Oxidative stress is involved in the progression of Parkinson’s disease (PD). Recent studies have confirmed that molecular hydrogen (H
2
) functions as a highly effective antioxidant in ...animal models of PD. A placebo-controlled, randomized, double-blind, parallel-group clinical pilot study was conducted to assess the efficacy of hydrogen gas inhalation in Japanese patients with PD on treatment with levodopa.
Methods
Twenty participants fulfilling the Movement Disorder Society criteria were enrolled. Participants inhaled 6.5 (0.1) vol% hydrogen gas in 2 L/min of mixed air or placebo air for 16 weeks, twice a day for 1 h.
Results
Five participants were excluded due to deviation from the protocol of the total duration of inhalation < 112 h. No significant differences were seen in the change in the total Movement Disorder Society Unified Parkinson’s Disease Rating Scale score from baseline to the 16
th
week between the group that inhaled hydrogen gas and the group that inhaled placebo air (Mann–Whitney
U
test,
p
> 0.05). No adverse events were seen. The compliance to the protocol-based duration of inhalation time in all participants decreased with the elderly participants, the higher daily dose of levodopa, and the higher PDQ-39 items on emotions (
n
= 20,
p
< 0.05).
Conclusion
This pilot study revealed that the inhalation of molecular hydrogen gas was safe, but did not show any beneficial effects in patients with PD.
Trial registration:
UMIN ID: 000,039,217 (October 6, 2018)
Parkinson's disease (PD) is a progressive neurodegenerative disease presenting with motor and non-motor symptoms, including skin disorders (seborrheic dermatitis, bullous pemphigoid, and rosacea), ...skin pathological changes (decreased nerve endings and alpha-synuclein deposition), and metabolic changes of sebum. Recently, a transcriptome method using RNA in skin surface lipids (SSL-RNAs) which can be obtained non-invasively with an oil-blotting film was reported as a novel analytic method of sebum. Here we report transcriptome analyses using SSL-RNAs and the potential of these expression profiles with machine learning as diagnostic biomarkers for PD in double cohorts (PD n = 15, 50, controls n = 15, 50). Differential expression analysis between the patients with PD and healthy controls identified more than 100 differentially expressed genes in the two cohorts. In each cohort, several genes related to oxidative phosphorylation were upregulated, and gene ontology analysis using differentially expressed genes revealed functional processes associated with PD. Furthermore, machine learning using the expression information obtained from the SSL-RNAs was able to efficiently discriminate patients with PD from healthy controls, with an area under the receiver operating characteristic curve of 0.806. This non-invasive gene expression profile of SSL-RNAs may contribute to early PD diagnosis based on the neurodegeneration background.
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