Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15

自噬 细胞生物学 生物 胞质分裂 内质网 自噬相关蛋白13 液泡蛋白分选 突变 细胞质 遗传学 液泡 基因 细胞 细胞分裂 蛋白激酶A 蛋白质磷酸化 细胞凋亡 磷酸化
作者
Chiara Vantaggiato,Claudia Crimella,Giovanni Airoldi,Roman Polishchuk,Sara Bonato,Erika Brighina,Marina Scarlato,Olimpia Musumeci,António Toscano,Andrea Martinuzzi,Filippo M. Santorelli,Andrea Ballabio,Nereo Bresolin,Emilio Clementi,Maria Teresa Bassi
出处
期刊:Brain [Oxford University Press]
卷期号:136 (10): 3119-3139 被引量:85
标识
DOI:10.1093/brain/awt227
摘要

Hereditary spastic paraparesis type 15 is a recessive complicated form of the disease clinically characterized by slowly progressive spastic paraparesis and mental deterioration with onset between the first and second decade of life. Thinning of corpus callosum is the neuroradiological distinctive sign frequently associated with white matter abnormalities. The causative gene, ZFYVE26, encodes a large protein of 2539 amino acid residues, termed spastizin, containing three recognizable domains: a zinc finger, a leucine zipper and a FYVE domain. Spastizin protein has a diffuse cytoplasmic distribution and co-localizes partially with early endosomes, the endoplasmic reticulum, microtubules and vesicles involved in protein trafficking. In addition, spastizin localizes to the mid-body during the final step of mitosis and contributes to successful cytokinesis. Spastizin interacts with Beclin 1, a protein required for cytokinesis and autophagy, which is the major lysosome-mediated degradation process in the cell. In view of the Beclin 1-spastizin interaction, we investigated the possible role of spastizin in autophagy. We carried out this analysis by using lymphoblast and fibroblast cells derived from four different spastizin mutated patients (p.I508N, p.L243P, p.R1209fsX, p.S1312X) and from control subjects. Of note, the truncating p.R1209fsX and p.S1312X mutations lead to loss of spastizin protein. The results obtained indicate that spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation. In cells lacking spastizin or with mutated forms of the protein, spastizin interaction with Beclin 1 is lost although the formation of the Beclin 1-UVRAG-Rubicon complex can still be observed. However, in these cells we demonstrate an impairment of autophagosome maturation and an accumulation of immature autophagosomes. Autophagy defects with autophagosome accumulation can be observed also in neuronal cells upon spastizin silencing. These results indicate that autophagy is a central process in the pathogenesis of complicated forms of hereditary spastic paraparesis with thin corpus callosum.

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