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

المؤلفون: Flaviano Giorgini, Tiago F. Outeiro, Susanna Campesan, David J. Koss

المصدر: Movement disorders 36(8), 1744-1758 (2021). doi:10.1002/mds.28605

مصطلحات موضوعية: 0301 basic medicine, Lewy Body Disease, Neurite, Endosome, alpha-synuclein, GTPase, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, genetics [Lewy Body Disease], genetics [Parkinson Disease], medicine, Humans, endocytosis, ddc:610, metabolism [alpha-Synuclein], Alpha-synuclein, Lewy body, RAB39B, Autophagy, Neurodegeneration, neurodegeneration, Parkinson Disease, Lewy body diseases, medicine.disease, metabolism [Lewy Bodies], metabolism [rab GTP-Binding Proteins], 030104 developmental biology, Neurology, chemistry, rab GTP-Binding Proteins, alpha-Synuclein, genetics [alpha-Synuclein], Lewy Bodies, Neurology (clinical), Rab, genetics [rab GTP-Binding Proteins], Neuroscience, 030217 neurology & neurosurgery

الوصف: Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::174a93c41786ddafd79e4ed29cf4a7d4Test
https://pub.dzne.de/record/155579Test