The composition of the gut microbiota, including Akkermansia muciniphila (A. muciniphila), is altered in many neurological diseases and may be involved in the pathophysiological processes of ...Parkinson's disease (PD). A. muciniphila, a mucin-degrading bacterium, is a potential next-generation microbe that has anti-inflammatory properties and is responsible for keeping the body healthy. As the role of A. muciniphila in PD has become increasingly apparent, we discuss the potential link between A. muciniphila and various neurological diseases (including PD) in the current review.
Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system. It is mainly expressed by oligodendrocytes. Although previous studies ...have found regulatory roles for Nogo-A in neurite outgrowth inhibition, neuronal homeostasis, precursor migration, plasticity, and neurodegeneration, its functions in the process of oxidative injury are largely uncharacterized. In this study, oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats. We used hydrogen peroxide (H2O2) to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes. After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes, Nogo-A expression was increased, and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death. Furthermore, knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2. Intervention with a Nogo-66 antibody, a LINGO1 blocker, or Y27632, an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway, did not affect the death of oligodendrocytes. Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes. In conclusion, Nogo-A aggravated reactive oxygen species damage in oligodendrocytes, and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process. This study was approved by the Ethics Committee of Peking University People's Hospital, China (approval No. 2018PHC081) on December 18, 2018.
Parkinson's disease (PD) is a common neurodegenerative disease with limited treatment and no cure, hence, broadening PD drug spectrum is of great significance. At present, engineered microorganisms ...are attracting increasing attention. In this study, we constructed an engineered strain of Clostridium butyricum‐GLP‐1, a C. butyricum (a probiotic) that consistently expresses glucagon‐like peptide‐1 (GLP‐1, a peptide‐based hormone with neurological advantage) in anticipation of its use in PD treatment. We further investigated the neuroprotective mechanism of C. butyricum‐GLP‐1 on PD mice models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. The results indicated that C. butyricum‐GLP‐1 could improve motor dysfunction and ameliorate neuropathological changes by increasing TH expression and reducing the expression of α‐syn. Moreover, we confirmed that C. butyricum‐GLP‐1 improved microbiome imbalance of PD mice by decreasing the relative abundance of Bifidobacterium at the genus level, improved gut integrity, and upregulated the levels of GPR41/43. Surprisingly, we found it could exert its neuroprotective effects via promoting PINK1/Parkin mediated mitophagy and attenuating oxidative stress. Together, our work showed that C. butyricum‐GLP‐1 improves PD by promoting mitophagy, which provides an alternative therapeutic modality for PD.
Late-onset multiple acyl-coA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder. It is still unclear about the muscle magnetic resonance image (MRI) pattern of the ...distal lower limb pre- and post-treatment in patients with late-onset MADD. This study described the clinical and genetic findings in a cohort of patients with late-onset MADD, and aimed to characterize the MRI pattern of the lower limbs.
Clinical data were retrospectively collected from clinic centers of Peking University People's Hospital between February 2014 and February 2018. Muscle biopsy, blood acylcarnitines, and urine organic acids profiles, and genetic analysis were conducted to establish the diagnosis of MADD in 25 patients. Muscle MRI of the thigh and leg were performed in all patients before treatment. Eight patients received MRI re-examinations after treatment.
All patients presented with muscle weakness or exercise intolerance associated with variants in the electron transfer flavoprotein dehydrogenase gene. Muscle MRI showed a sign of both edema-like change and fat infiltration selectively involving in the soleus (SO) but sparing of the gastrocnemius (GA) in the leg. Similar sign of selective involvement of the biceps femoris longus (BFL) but sparing of the semitendinosus (ST) was observed in the thigh. The sensitivity and specificity of the combination of either "SO+/GA-" sign or "BFL+/ST-" sign for the diagnosis of late-onset MADD were 80.0% and 83.5%, respectively. Logistic regression model supported the findings. The edema-like change in the SO and BFL muscles were quickly recovered at 1 month after treatment, and the clinical symptom was also relieved.
This study expands the clinical and genetic spectrums of late-onset MADD. Muscle MRI shows a distinct pattern in the lower limb of patients with late-onset MADD. The dynamic change of edema-like change in the affected muscles might be a potential biomarker of treatment response.
Mitochondrial myopathy is a group of diseases caused by abnormal mitochondrial structure or function. The mitochondrial myopathy impacts muscles of the whole body and exhibits variable symptoms. ...Respiratory muscle deficits deteriorate pulmonary function in patients with severe pneumonia.
We report the case of a male patient with severe pneumonia-induced respiratory failure. He was abnormally dependent invasive ventilator-assisted ventilation after his condition had improved. Then we found abnormal ventilator waveform and a decline in muscle strength of him. Mitochondrial myopathy was ultimately confirmed by muscle pathological biopsy and body fluid genetic testing. Vitamin B complex, coenzyme Q10, Neprinol AFD, l-arginine, and MITO-TONIC were used to improve mitochondrial function and muscle metabolism. After treatment, discomfort associated with chest tightness, fatigue, cough, and sputum disappeared, and the patient was discharged.
This case presented an uncommon cause of difficult weaning and extubation—acute onset of mitochondrial myopathy. Muscle biopsy and genetic testing of body fluid are essential for diagnosing mitochondrial myopathy. The A3243G mutation in the MT-TL1 gene of mitochondrial DNA contributes to pathogenesis of this case.
Definitive diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrP
Sc
). Our previous study revealed that PrP
Sc
...-seeding activity (PrP
Sc
-SA) is detectable in skin of sCJD patients by an ultrasensitive PrP
Sc
seed amplification assay (PrP
Sc
-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2–3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrP
Sc
-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrP
Sc
-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrP
Sc
types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrP
Sc
-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives 12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4,
p
< 0.001. Our study validates skin PrP
Sc
-SA as a biomarker for the detection of prion diseases, which is influenced by the PrP
Sc
types,
PRNP
129 polymorphisms, dermatome sampled, and disease duration.
Neuronal intranuclear inclusion disease is a rare hereditary neurodegenerative disease characterized by localized eosinophilic intracytoplasmic inclusion bodies in cells of the nervous system and ...internal organs. This disorder is frequently missed or misdiagnosed, as there is significant heterogeneity of its clinical presentation. Recently, genetic sequencing has revealed complex links between neuronal intranuclear inclusion disease and other neurodegenerative diseases, potentially explaining the diversity of clinical manifestations. Herein, we describe the case of a 68-year-old male Chinese patient who was initially diagnosed with Parkinson's disease based on classic symptomatology and ¹²³I-metaiodobenzylguanidine scintigraphy results and was subsequently treated with oral methyldopa for 3 years. He developed a paroxysmal tic before he presented to our hospital for treatment after a convulsive seizure. Brain magnetic resonance imaging identified signal hyperintensity at the corticomedullary junction on diffusion-weighted imaging. Skin biopsy results and genetic testing confirmed a revised diagnosis of neuronal intranuclear inclusion disease. This report highlights that patients clinically diagnosed with Parkinson's disease may actually be in the early stages of neuronal intranuclear inclusion disease, suggesting that patients with suspected Parkinson's disease should also be screened for this disease.
Background
We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy (UCMD).
Methods
Clinical data of probands were collected ...and muscle biopsies of patients were analyzed. Exons of
COL6A1
,
COL6A2
and
COL6A3
were analyzed by direct sequencing. Mutations in
COL6A1
,
COL6A2
and
COL6A3
were identified in 8 patients.
Results
Among these mutations, 5 were novel three in the triple helical domain (THD) and 2 in the second C-terminal (C2) domain. We also identified five known missense or in-frame deletion mutations in THD and C domains. Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions.
Conclusions
The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI, thereby providing useful information for the genetic counseling of UCMD patients.
Accumulating evidence indicates that the aberrant re-entry of post-mitotic neurons into the G2/M phase of cell cycle and the resulting mitotic catastrophe may contribute to the pathogenesis of ...Alzheimer's disease. However, the cellular event that drives the differentiated neurons to abnormally enter G2/M phase remains elusive. Similarly, whether mitotic catastrophe is indeed one of the death pathways for differentiated neurons is not clear. Previous studies revealed that okadaic acid (OA), a phosphatase inhibitor that induces AD like pathological changes, evokes mitotic changes in neuroblastoma cells. In this study, we examined the
in vivo effects of OA on cyclin B1 expression, the induction of mitosis, and subsequent mitotic catastrophe. We found that cyclin B1 expression in adult neurons was significantly increased after injecting OA into rat frontal cortex, which also increased tau protein phosphorylation. Interestingly, cyclin B1 and phosphorylated tau were well co-localized around the OA injection site, but were only partially co-localized in other brain regions. Staining with toluidine blue, Giemsa dye or propidium iodide revealed typical mitotic and mitotic catastrophe-like morphological changes with irregular arrangement of condensed chromatin and chromosome fibers in a few cells. Furthermore, the strong cyclin B1 staining in these cells suggests that cyclin B1 promoted G2 to M phase transition is required for the mitotic catastrophe. The detection of neuron-specific enolase in a portion of these cells demonstrated that at least part them are neuron. All together, our results suggest that the disturbance of the protein kinase-phosphatase system caused by OA is sufficient to induce neuronal cyclin B1 expression, force neurons into the mitotic phase of cell cycle, and cause mitotic catastrophe.
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