Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer’s disease as a mitophagy receptor

Zhao Tao Wang, Mei Hong Lu, Yan Zhang, Wen Li Ji, Lei Lei, Wang Wang, Li Pao Fang, Lu Wen Wang, Fan Yu, Ji Wang, Zhen Yu Li, Jian Rong Wang, Ting Hua Wang, Fei Dou, Qin Wen Wang, Xing Long Wang, Shao Li, Quan Hong Ma, Ru Xiang Xu

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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 ( 210 FSFI 213 ), 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.

Original languageEnglish (US)
Article numbere12860
JournalAging cell
Volume18
Issue number1
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • Disrupted-in-schizophrenia-1
  • autophagy
  • mitochondria
  • mitophagy

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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