TAR DNA-Binding Protein 43 and Disrupted in Schizophrenia 1 Coaggregation Disrupts Dendritic Local Translation and Mental Function in Frontotemporal Lobar Degeneration

Ryo Endo, Noriko Takashima, Yoko Nekooki-Machida, Yusuke Komi, Kelvin Kai Wan Hui, Masaki Takao, Hiroyasu Akatsu, Shigeo Murayama, Akira Sawa, Motomasa Tanaka

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Neurodegenerative diseases involving protein aggregation often accompany psychiatric symptoms. Frontotemporal lobar degeneration (FTLD) associated with TAR DNA-binding protein 43 (TDP-43) aggregation is characterized by progressive neuronal atrophy in frontal and temporal lobes of cerebral cortex. Furthermore, patients with FTLD display mental dysfunction in multiple behavioral dimensions. Nevertheless, their molecular origin for psychiatric symptoms remains unclear. Methods: In FTLD neurons and mouse models with TDP-43 aggregates, we examined coaggregation between TDP-43 and disrupted in schizophrenia 1 (DISC1), a key player in the pathology of mental conditions and its effects on local translation in dendrites and psychiatric behaviors. The protein coaggregation and the expression level of synaptic proteins were also investigated with postmortem brains from patients with FTLD (n = 6). Results: We found cytosolic TDP-43/DISC1 coaggregates in brains of both FTLD mouse model and patients with FTLD. At the mechanistic levels, the TDP-43/DISC1 coaggregates disrupted the activity-dependent dendritic local translation through impairment of translation initiation and, in turn, reduced synaptic protein expression. Behavioral deficits detected in FTLD model mice were ameliorated by exogenous DISC1 expression. Conclusions: Our findings reveal a novel role of the aggregate-prone TDP-43/DISC1 protein complex in regulating local translation, which affects aberrant behaviors relevant to multiple psychiatric dimensions.

Original languageEnglish (US)
Pages (from-to)509-521
Number of pages13
JournalBiological psychiatry
Volume84
Issue number7
DOIs
StatePublished - Oct 1 2018

Keywords

  • Coaggregation
  • DISC1
  • FTLD
  • Local translation
  • Psychiatric behaviors
  • TDP-43

ASJC Scopus subject areas

  • Biological Psychiatry

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