散装脂质转运体VPS13A和BLTP2在神经退行性和神经发育中的作用。

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2025-03-28 DOI:10.1002/mds.30178

Sarah D. Neuman PhD, Rajan S. Thakur PhD, Scott J. Gratz PhD, Kate M. O'Connor-Giles PhD, Arash Bashirullah PhD

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引用次数: 0

摘要

背景：桥状脂质转移蛋白（BLTPs）在膜接触部位介导大量脂质转运。BLTPs的突变与早发性神经发育和晚发性神经退行性疾病（包括运动障碍）有关。BLTPs在疾病发病机制中的组织特异性和时间要求仍然知之甚少。目的：本研究的目的是通过果蝇模型确定VPS13A和BLTP2在组织特异性和衰老依赖性中的作用。方法：我们在果蝇的神经元和肌肉中产生了VPS13A同源基因（Vps13）和BLTP2同源基因（hobbit）的组织特异性敲低。我们分析了年龄依赖性运动行为、神经退行性变和突触发育和功能。结果：神经元特异性的VPS13A同源物缺失导致神经退行性变，随后出现年龄依赖性运动缺陷和寿命缩短，而肌肉特异性的缺失仅影响寿命。相比之下，BLTP2同源体的神经元缺失导致了严重的早发性运动缺陷，但没有神经退行性变，而肌肉缺失则损害了神经肌肉连接处的突触发生和神经传递。结论：VPS13A维持神经元存活，而BLTP2协调突触发育。BLTP功能的表型特异性为BLTP相关疾病的不同疾病轨迹提供了机制见解。©2025作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

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Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2

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Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2

Background

Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood.

Objective

The objective of this study was to determine tissue-specific and aging-dependent roles for VPS13A and BLTP2 using Drosophila models.

Methods

We generated tissue-specific knockdowns of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) in neurons and muscles of Drosophila. We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function.

Results

Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by aging-dependent movement deficits and reduced lifespan, whereas muscle-specific loss affected only lifespan. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, whereas muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction.

Conclusions

VPS13A maintains neuronal survival, whereas BLTP2 orchestrates synaptic development. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.