RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies
| العنوان: | RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies |
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| المؤلفون: | Odeta Bondarevaite, Flaviano Giorgini, Marta Leite, Sara Adams, Tiago F. Outeiro, Johannes Attems, David J. Koss |
| المصدر: | Brain Pathology |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| 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. |
| تدمد: | 1750-3639 1015-6305 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a6f721b5e83361fcaa5b2abc95630f1Test https://doi.org/10.1111/bpa.12890Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9a6f721b5e83361fcaa5b2abc95630f1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17503639 10156305 |
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