المؤلفون: E. De Vita, Rachael I. Scahill, Filipe B. Rodrigues, R. Tortelli, Mariette Heins, Gunnar Flik, A. J. Lowe, Lauren M. Byrne, Flaviano Giorgini, Eileanoir B. Johnson, Edward J. Wild

المصدر: Journal of Neurochemistry

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Kynurenine pathway, Pharmacology, Biochemistry, cerebrospinal fluid, Cohort Studies, Pathogenesis, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Kynurenic acid, Cerebrospinal fluid, Huntington's disease, blood, medicine, Humans, Prospective Studies, Kynurenine, Chromatography, High Pressure Liquid, Aged, business.industry, Clinical Studies, Biomakers & Imaging, biomarkers, Human brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Huntington Disease, Phenotype, 030104 developmental biology, medicine.anatomical_structure, chemistry, Original Article, Female, ORIGINAL ARTICLES, business, 030217 neurology & neurosurgery, Signal Transduction, Quinolinic acid

الوصف: Converging lines of evidence from several models, and post‐mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single‐site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high‐performance liquid‐chromatography to measure the levels of KP metabolites—tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, anthranilic acid and quinolinic acid—in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short‐term stability, intergroup differences, associations with clinical and imaging measures and derived sample‐size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids.
Converging lines of evidence from non‐human models support the involvement of the kynurenine pathway in Huntington's disease. However, evidence in living humans is limited. In a prospective study with standardised collection of cerebrospinal fluid and blood, we used high‐performance liquid‐chromatography to analyse this pathway. We concluded that the selected metabolites are readily and reliably quantifiable. Yet, we found little evidence to support a substantial derangement of the kynurenine pathway in Huntington's disease, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids. 3‐HK, 3‐hydroxykynurenine; KYNA, kynurenic acid; QUIN, quinolinic acid.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6eaf51725f7f138eabd61f8be52c8ce9Test
https://doi.org/10.1111/jnc.15360Test

المؤلفون: Odeta Bondarevaite, Flaviano Giorgini, Marta Leite, Sara Adams, Tiago F. Outeiro, Johannes Attems, David J. Koss

المصدر: Brain Pathology

مصطلحات موضوعية: Lewy Body Disease, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Parkinson's disease, Plaque, Amyloid, Biology, Pathology and Forensic Medicine, Pathogenesis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Research Articles, Aged, Aged, 80 and over, Alpha-synuclein, Temporal cortex, Amyloid beta-Peptides, proteostasis, Lewy body, alpha‐Synuclein, Dementia with Lewy bodies, RAB39B, General Neuroscience, Neurodegeneration, Brain, Human brain, Middle Aged, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, rab GTP-Binding Proteins, Parkinson’s disease, Female, Lewy Bodies, Neurology (clinical), Lewy body dementia, 030217 neurology & neurosurgery, Research Article

الوصف: Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X‐linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha‐Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post‐mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co‐localized with beta‐amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B‐associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co‐aggregation of RAB39B with Aβ in plaques suggests that age‐associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a6f721b5e83361fcaa5b2abc95630f1Test
https://doi.org/10.1111/bpa.12890Test