科研之友
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摘要
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 A-treated cultured cells. Disrupted-in-schizophrenia-1 contains a canonical LC3-interacting region (LIR) motif ((FSFI213)-F-210), 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 A-induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues A-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 4months rescues cognitive deficits, synaptic loss, and A 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 A accumulation-induced toxicity through promoting mitophagy.
