Shah Nikita, Kasture Ameya S, Fischer Florian P, Sitte Harald H, Hummel Thomas, Sucic Sonja
Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Epileptology and Neurology, RWTH Aachen University, Aachen, Germany.
Front Mol Neurosci. 2024 Aug 29;17:1466694. doi: 10.3389/fnmol.2024.1466694. eCollection 2024.
As the first member of the solute carrier 6 (SLC6) protein family, the γ-aminobutyric acid (GABA) transporter 1 (GAT1, ), 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 gene is highly susceptible to missense mutations, leading to severe clinical outcomes, such as epilepsy, in the afflicted patients. The molecular mechanisms of -associated disorders are discerned to some degree; many 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 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 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 -related disorders.
作为溶质载体6（SLC6）蛋白家族的首个成员，γ-氨基丁酸（GABA）转运体1（GAT1）在将GABA从突触间隙摄取到神经元和星形胶质细胞的过程中发挥着关键作用。这一过程有助于随后将GABA储存于突触前囊泡中。人类GAT1基因极易发生错义突变，导致患病患者出现严重的临床后果，如癫痫。GAT1相关疾病的分子机制在一定程度上已被洞悉；现已发现许多GAT1突变会损害蛋白质折叠，进而无法到达质膜。本质上，一旦进入内质网（ER），GAT1就会遵循一系列复杂的事件，以实现高效的细胞内运输。这涉及与负责引导蛋白质折叠过程、寡聚化、通过高尔基体分选并最终递送至细胞表面的特殊分子伴侣结合。整个过程在多个检查点受到严格的质量控制机制的约束。虽然大多数现有的功能丧失型GAT1变体干扰折叠和膜靶向，但某些突变体仍保留丰富的表面表达。在任何一种情况下，GAT1活性的抑制都会破坏GABA能神经传递，先于携带这些突变的个体出现疾病表现。神经系统引人入胜，需要系统的、开创性的研究工作来剖析与复杂神经系统疾病发病相关的精确分子因素，并发现更多非经典治疗靶点。最近的研究为一些错误折叠的GAT1变体带来了希望，这些变体可以通过作用于分泌途径中多个上游靶点的小分子，即化学和药理伴侣来挽救。我们在此强调药物伴侣疗法作为治疗GAT1相关疾病治疗策略的重要性。
