转运体的厄运或命运:健康和疾病中的 SLC6A1、新型分子靶点和新的治疗前景

IF 3.5 3区 医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-08-29 DOI:10.3389/fnmol.2024.1466694
Nikita Shah, Ameya S. Kasture, Florian P. Fischer, Harald H. Sitte, Thomas Hummel, Sonja Sucic
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引用次数: 0

摘要

作为溶质运载体 6(SLC6)蛋白家族的第一个成员,γ-氨基丁酸(GABA)转运体 1(GAT1,SLC6A1)在将 GABA 从突触间隙摄取到神经元和星形胶质细胞中的过程中起着关键作用。这一过程有助于 GABA 随后储存在突触前囊泡中。人类 SLC6A1 基因极易发生错义突变,导致患者出现癫痫等严重临床后果。SLC6A1 相关疾病的分子机制已在一定程度上得到揭示;目前已知许多 SLC6A1 基因突变会影响蛋白质的折叠,从而无法到达质膜。从本质上讲,一旦进入内质网(ER),GAT1 就会遵守一连串复杂的程序,从而实现有效的细胞内转运。这包括与专门的分子伴侣结合,负责引导蛋白质折叠过程、寡聚化、通过高尔基体分拣,并最终输送到细胞表面。整个过程在多个检查点都要经过严格的质量控制机制。虽然现有的大多数功能缺失 SLC6A1 变体都会干扰折叠和膜靶向,但某些突变体仍保留了丰富的表面表达。无论在哪种情况下,GAT1 的活性受到抑制,都会破坏 GABA 能神经递质,从而使携带这些突变的个体提前出现疾病表现。神经系统令人着迷,需要进行系统的、开创性的研究,以剖析与复杂神经系统疾病发病相关的精确分子因素,并发现更多的非经典治疗靶点。最近的研究为一些折叠错误的 SLC6A1 变体带来了希望,它们可以通过小分子(即化学和药理伴侣)作用于分泌途径中的多个上游靶点来挽救。我们在此强调药理合剂作为一种治疗策略对治疗 SLC6A1 相关疾病的重要意义。
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A transporter’s doom or destiny: SLC6A1 in health and disease, novel molecular targets and emerging therapeutic prospects
As the first member of the solute carrier 6 (SLC6) protein family, the γ-aminobutyric acid (GABA) transporter 1 (GAT1, SLC6A1), plays a pivotal role in the uptake of GABA from the synaptic cleft into neurons and astrocytes. This process facilitates the subsequent storage of GABA in presynaptic vesicles. The human SLC6A1 gene is highly susceptible to missense mutations, leading to severe clinical outcomes, such as epilepsy, in the afflicted patients. The molecular mechanisms of SLC6A1-associated disorders are discerned to some degree; many SLC6A1 mutations are now known to impair protein folding, and consequently fail to reach the plasma membrane. Inherently, once inside the endoplasmic reticulum (ER), GAT1 abides by a complex cascade of events that enable efficient intracellular trafficking. This involves association with specialized molecular chaperones responsible for steering the protein folding process, oligomerization, sorting through the Golgi apparatus, and ultimately delivery to the cell surface. The entire process is subject to stringent quality control mechanisms at multiple checkpoints. While the majority of the existing loss-of-function SLC6A1 variants interfere with folding and membrane targeting, certain mutants retain abundant surface expression. In either scenario, suppressed GAT1 activity disrupts GABAergic neurotransmission, preceding the disease manifestation in individuals harboring these mutations. The nervous system is enthralling and calls for systematic, groundbreaking research efforts to dissect the precise molecular factors associated with the onset of complex neurological disorders, and uncover additional non-canonical therapeutic targets. Recent research has given hope for some of the misfolded SLC6A1 variants, which can be salvaged by small molecules, i.e., chemical and pharmacological chaperones, acting on multiple upstream targets in the secretory pathway. We here highlight the significance of pharmacochaperoning as a therapeutic strategy for the treatment of SLC6A1-related disorders.
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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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