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.

中文翻译：

---

RAB39B 在路易体痴呆中重新分布，并被隔离在 aβ 斑块和路易体中

大脑 39B (RAB39B) 囊泡运输蛋白 Ras 类比中的功能缺失突变与罕见的 X 连锁帕金森病 (PD) 相关。生理学上，RAB39B 定位于高尔基体囊泡和循环内体，是谷氨酸受体成熟所必需的，也是 α-突触核蛋白 (aSyn) 稳态和抑制其聚集所必需的。尽管有证据表明 RAB39B 与神经退行性疾病有关，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，对来自路易体痴呆（DLB，n = 10）、阿尔茨海默病（AD，n = 12）和对照组（n = 12）的死后人脑组织进行了 RAB39B 的空间分布和表达分析）。使用组织微阵列对皮质 RAB39B 免疫反应性的评估显示，与对照组和 AD 病例相比，DLB 病例中 RAB39B 阳性灰质面积总体减少。引人注目的是，在所有检查的病例中，RAB39B 与 β-淀粉样蛋白 (Aβ) 斑块共定位，并且还存在于 DLB 的路易体 (LBs) 亚群中。在 DLB、AD 和对照之间，颞叶皮层内总 RAB39B 水平的生化测量值没有变化。然而，在亚细胞分离后，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磷酸化的 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，并且 RAB39B 与斑块中 Aβ 的共聚集表明与年龄相关的脑 Aβ 病理学可能是导致 RAB39B 丢失的原因。因此，RAB39B、其相关的功能通路及其在聚集体中的捕获可被视为治疗干预的未来目标，以阻止路易体疾病的整体病理负担和细胞功能障碍。