The modular complex TRAPP acts as an activator of a subgroup of Ypt/RAB GTPases. The substrate GTPases and TRAPP are conserved from yeast to human cells, required for secretion and macroautophagy/autophagy and implicated in human disease. All TRAPP complexes contain four core subunits essential for cell viability, and until recently there were no human diseases associated with any core TRAPP subunit. Recently, we reported a neurological disorder associated with a pathogenic variant of the core TRAPP subunit TRAPPC4. This variant results in lower levels of full-length TRAPPC4 protein and the TRAPP complex. A conditional mutation of the yeast homolog of TRAPPC4, Trs23, also results in a lower level of the protein and the TRAPP complex. Phenotypic analysis of the yeast mutant cells reveals a minor defect in secretion and a major defect in autophagy. Similarly, primary fibroblasts derived from human patients also exhibit minor and severe defects in secretion and autophagy, respectively. We propose that the autophagy defect caused by the pathogenic-TRAPPC4 variant results in the severe neurological disorder. Moreover, we hypothesize that low levels of the core TRAPP complex are more detrimental to autophagy than to secretion, and that the long-term autophagy defect is especially harmful to neuronal cells.

中文翻译：

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捕捉神经系统疾病：从酵母到人类。

模块化复合物TRAPP充当Ypt / RAB GTPases子组的激活剂。底物GTPases和TRAPP从酵母到人类细胞都是保守的，是分泌和大自噬/自噬所必需的，并且与人类疾病有关。所有的TRAPP复合物都含有四个对细胞活力至关重要的核心亚基，直到最近还没有人类疾病与任何核心TRAPP亚基相关。最近，我们报道了与核心TRAPP亚基TRAPPC4的致病变异相关的神经系统疾病。该变体导致全长TRAPPC4蛋白和TRAPP复合物的水平降低。TRAPPC4的酵母同源物Trs23的条件突变也导致蛋白质和TRAPP复合物的水平降低。酵母突变细胞的表型分析显示分泌的次要缺陷和自噬的主要缺陷。同样，源自人类患者的原代成纤维细胞在分泌和自噬方面也分别表现出轻微和严重的缺陷。我们建议由致病性TRAPPC4变体引起的自噬缺陷导致严重的神经系统疾病。此外，我们假设核心TRAPP复合物的低水平对自噬比对分泌更有害，并且长期自噬缺陷对神经元细胞尤其有害。