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

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

doi:10.1016/j.biopsych.2018.03.008

Cited by 29 publications

(24 citation statements)

References 62 publications

(85 reference statements)

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“…TDP-43 aggregates are the most common forms of neuropathological abnormalities in FTD, and animal models with mutation in the gene encoding this protein (TARDBP) are important tools to help understand the role of this protein in behavioral symptoms of FTD. Indeed, TDP-43 was found to co-aggregate with the disrupted in schizophrenia 1 (DISC1) protein in the cytosol of neurons in brains of both FTLD mouse model and patients (Endo et al, 2018). Examination of the animal data revealed that, co-aggregation of TDP-43/DISC1 reduced synaptic protein expression by disrupting activity-dependent dendritic local translation.…”

Section: Neuropathology Of Frontotemporal Dementiamentioning

confidence: 99%

A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia

Nascimento

Nunes

Rodriguez

et al. 2019

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Mental disorders are highly prevalent and important causes of medical burden worldwide. Cooccurrence of neurological and psychiatric symptoms are observed among mental disorders, representing a challenge for their differential diagnosis. Psychiatrists and neurologists have faced challenges in diagnosing old adults presenting behavioral changes. This is the case for early frontotemporal dementia (FTD) and bipolar disorder. In its initial stages, FTD is characterized by behavioral or language disturbances in the absence of cognitive symptoms. Consequently, patients with the behavioral subtype of FTD (bv-FTD) can be initially misdiagnosed as having a psychiatric disorder, typically major depression disorder (MDD) or bipolar disorder (BD). Bipolar disorder is associated with a higher risk of dementia in older adults and with cognitive impairment, where a subset of patients presents a neuroprogressive pattern during the disease course. No mendelian mutations were identified in BD, whereas three major genetic causes of FTD have been identified. Clinical similarities between BD and bv-FTD raise the question whether common molecular pathways might explain shared clinical symptoms. Here, we reviewed existing data on clinical and molecular similarities between BD and FTD to propose biological pathways that can be further investigated as common or specific markers of BD and FTD.

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Section: Neuropathology Of Frontotemporal Dementiamentioning

confidence: 99%

A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia

Nascimento

Nunes

Rodriguez

et al. 2019

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…In addition, several recent studies have highlighted the importance of proper translational control in regulating behaviours associated with neuropsychiatric and mood disorders [29,30,31]. Trinh and colleagues [30] demonstrated that the disruption of translational regulation by a brain-specific deficiency of PKR-like ER kinase (PERK) resulted in impaired behavioural flexibility among other behavioural deficits.…”

Section: Translational Dysregulation In Neurological Disordersmentioning

confidence: 99%

Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

et al. 2019

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De novo protein synthesis by the ribosome and its multitude of co-factors must occur in a tightly regulated manner to ensure that the correct proteins are produced accurately at the right time and, in some cases, also in the proper location. With novel techniques such as ribosome profiling and cryogenic electron microscopy, our understanding of this basic biological process is better than ever and continues to grow. Concurrently, increasing attention is focused on how translational regulation in the brain may be disrupted during the progression of various neurological disorders. In fact, translational dysregulation is now recognized as the de facto pathogenic cause for some disorders. Novel mechanisms including ribosome stalling, ribosome-associated quality control, and liquid-liquid phase separation are closely linked to translational regulation, and may thus be involved in the pathogenic process. The relationships between translational dysregulation and neurological disorders, as well as the ways through which we may be able to reverse those detrimental effects, will be examined in this review.

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“…Taken together, these data imply that disturbed local mRNA translation contributes to pathology of ALS. It is worthy to note that TDP-43 is also crucial for regulating dendritic local translation in response to neuronal activity (Endo et al, 2018). This may suggest the role of TDP-43 for psychiatric outcomes observed in FTD patients.…”

Section: Amyotrophic Lateral Sclerosis (Als) and Frontotemporal Demenmentioning

confidence: 93%

The Role of RNA Binding Proteins for Local mRNA Translation: Implications in Neurological Disorders

Thelen

Kye

2020

Front. Mol. Biosci.

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As neurons are one of the most highly polarized cells in our body, they require sophisticated cellular mechanisms to maintain protein homeostasis in their subcellular compartments such as axons and dendrites. When neuronal protein homeostasis is disturbed due to genetic mutations or deletions, this often results in degeneration of neurons leading to devastating outcome such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and fragile X syndrome (FXS). Ribonucleoprotein (RNP) complexes are macromolecular complexes composed of RNA binding proteins (RBPs) and their target RNAs. RBPs contain RNA binding domains and bind to RNA molecules via specific sequence motifs. RNP complexes have various functions in gene expression including messenger RNA (mRNA) trafficking, RNA processing and silencing. In neurons, RBPs deliver specific sets of mRNAs to subcellular compartments such as axons and dendrites to be locally translated. Mutations or deletions in genes coding for RNPs have been reported as causes for neurological disorders such as SMA, ALS, and FXS. As RBPs determine axonal or dendritic mRNA repertoires as well as proteomes by trafficking selective mRNAs and regulating local protein synthesis, they play a crucial role for neuronal function. In this review, we summarize the role of well-known RBPs, SMN, TDP-43, FUS, and FMRP, and review their function for local protein synthesis in neurons. Furthermore, we discuss their pathological contribution to the neurological disorders.

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

Abstract: 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.

Cited by 29 publications

References 62 publications

A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia

A review on shared clinical and molecular mechanisms between bipolar disorder and frontotemporal dementia

Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances

The Role of RNA Binding Proteins for Local mRNA Translation: Implications in Neurological Disorders

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