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Biol Psychiatry. 2018 Oct 1;84(7):509-521. doi: 10.1016/j.biopsych.2018.03.008. Epub 2018 Mar 29.

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

Author information

1
Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Wako, Japan.
2
Department of Neurology, Saitama Medical University, Moroyama, Saitama, Japan; Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
3
Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan; Department of Medicine for Aging in Place and Community-Based Medical Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
4
Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
5
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: asawa1@jhmi.edu.
6
Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Wako, Japan. Electronic address: motomasa@brain.riken.jp.

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.

KEYWORDS:

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

PMID:
29752072
PMCID:
PMC6123275
[Available on 2019-10-01]
DOI:
10.1016/j.biopsych.2018.03.008

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