Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science , Wako, Saitama , Japan.
Autophagy. 2019 Oct;15(10):1848-1849. doi: 10.1080/15548627.2019.1637643. Epub 2019 Jul 7.
The disruption of MTOR-regulated macroautophagy/autophagy was previously shown to cause autistic-like abnormalities; however, the underlying molecular defects remained largely unresolved. In a recent study, we demonstrated that autophagy deficiency induced by conditional deletion in either forebrain GABAergic inhibitory or excitatory neurons leads to a similar set of autistic-like behavioral abnormalities even when induced following the peak period of synaptic pruning during postnatal neurodevelopment. Our proteomic analysis and molecular dissection further revealed a mechanism in which the GABA receptor trafficking function of GABARAP (gamma-aminobutyric acid receptor associated protein) family proteins was compromised as they became sequestered by SQSTM1/p62-positive aggregates formed due to autophagy deficiency. Our discovery of autophagy as a link between MTOR and GABA signaling may have implications not limited to neurodevelopmental and neuropsychiatric disorders, but could potentially be involved in other human pathologies such as cancer and diabetes in which both pathways are implicated.
先前的研究表明，MTOR 调控的巨自噬/自噬的破坏会导致类似自闭症的异常；然而，其潜在的分子缺陷在很大程度上仍未得到解决。在最近的一项研究中，我们证明了在前脑 GABA 能抑制性或兴奋性神经元中条件性缺失诱导的自噬缺失，即使在出生后神经发育期间突触修剪高峰期后诱导，也会导致类似的一组自闭症样行为异常。我们的蛋白质组学分析和分子剖析进一步揭示了一种机制，即 GABA 受体易位功能的 GABAARAP（γ-氨基丁酸受体相关蛋白）家族蛋白由于自噬缺失导致 SQSTM1/p62 阳性聚集体形成而被隔离。我们发现自噬是 MTOR 和 GABA 信号之间的联系，这一发现不仅对神经发育和神经精神疾病有影响，而且可能与其他人类疾病（如癌症和糖尿病）有关，这些疾病都与这两条途径有关。
