Department of Neurosurgery, Affiliated Bayi Brain Hospital, General Army Hospital, Southern Medical University, Beijing, China.
Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.
Aging Cell. 2019 Feb;18(1):e12860. doi: 10.1111/acel.12860. Epub 2018 Nov 28.
Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We show levels of Disrupted-in-schizophrenia-1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aβ-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif ( FSFI ), through which DISC1 directly binds to LC3-I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking-down of DISC1 blocks Aβ-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aβ-induced mitochondrial dysfunction, loss of spines, suppressed long-term potentiation (LTP). Overexpression of DISC1 via adeno-associated virus (serotype 8, AAV8) in the hippocampus of 8-month-old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aβ plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aβ accumulation-induced toxicity through promoting mitophagy.
线粒体功能障碍是阿尔茨海默病（AD）的早期特征。与受损的线粒体相关的累积损伤，与 AD 中的神经退行性变有关。我们发现，与精神疾病和 AD 相关的基因 Disrupted-in-schizophrenia-1（DISC1）的水平在 AD 患者和转基因模型小鼠以及 Aβ 处理的培养细胞的大脑中降低。Disrupted-in-schizophrenia-1 包含一个经典的 LC3 相互作用区域（LIR）基序（FSFI），通过该基序，DISC1 直接与 LC3-I/II 结合。DISC1 的过表达通过与 LC3 的结合增强自噬，而 DISC1 的敲低则阻断 Aβ 诱导的自噬。我们进一步观察到 DISC1 的过表达，但不是其突变体（muFSFI），其消除了 DISC1 与 LC3 的相互作用，挽救了 Aβ 诱导的线粒体功能障碍、棘突丢失和长时程增强（LTP）的抑制。通过腺相关病毒（血清型 8，AAV8）在 8 个月大的 APP/PS1 转基因小鼠的海马体中表达 DISC1 4 个月，以依赖于 DISC1 与 LC3 相互作用的方式，挽救了认知缺陷、突触丢失和 Aβ 斑块积累。这些结果表明，DISC1 是一种新型的自噬受体，通过促进自噬来保护突触可塑性免受 Aβ 积累诱导的毒性。
