Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
Department of Genetics and Genome Biology, University of Leicester, University Road, Leicester, LE1 7RH, UK.
Brain Pathol. 2021 Jan;31(1):120-132. doi: 10.1111/bpa.12890. Epub 2020 Aug 25.
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.
Ras 类比物在脑 39B 中的囊泡运输蛋白（RAB39B）中的功能丧失突变与罕见的 X 连锁帕金森病（PD）有关。生理上，RAB39B 定位于高尔基体囊泡和再循环内体，是谷氨酸能受体成熟所必需的，但也是α-突触核蛋白（aSyn）的动态平衡和抑制其聚集所必需的。尽管有证据表明 RAB39B 与神经退行性变有关，但该蛋白在特发性神经退行性疾病中的作用仍未确定。在这里，对尸检人脑组织中痴呆伴路易体（DLB，n=10）、阿尔茨海默病（AD，n=12）和对照组（n=12）中 RAB39B 的空间分布和表达进行了分析。使用组织微阵列评估皮质 RAB39B 免疫反应性显示，与对照组和 AD 病例相比，DLB 病例中 RAB39B 阳性灰质的面积总体减少。引人注目的是，RAB39B 与所有检查病例中的β-淀粉样蛋白（Aβ）斑块共定位，并且在 DLB 中的路易体（LB）亚群中也存在。颞叶皮质内总 RAB39B 水平的生化测量在 DLB、AD 和对照组之间没有变化。然而，在亚细胞分级分离后，在 DLB 病例中发现细胞质池中的 RAB39B 减少，同时整个组织裂解物中的磷酸化 aSyn 和 Aβ 增加。细胞质 RAB39B 的减少与 RAB39B 相关功能的储备能力受损一致，这反过来可能促进 LB 聚集和突触损伤。总的来说，我们的数据支持 RAB39B 参与 DLB 的发病机制，以及 RAB39B 与斑块中的 Aβ 共聚集表明与年龄相关的大脑 Aβ 病理学可能有助于 RAB39B 的丧失。因此，RAB39B、其相关功能途径及其在聚集体中的捕获可以被认为是未来治疗干预的靶点，以阻止路易体疾病中的总体病理负担和细胞功能障碍。
