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277 results on '"Tsai, Kuen-Jer"'

1. Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP

Author

Chu, Yuan-Ping, Jin, Lee-Way, Wang, Liang-Chao, Ho, Pei-Chuan, Wei, Wei-Yen, and Tsai, Kuen-Jer

Subjects
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Mice, Animals, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Prealbumin, TDP-43 Proteinopathies, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Autophagy, Activating Transcription Factor 4, ATF4, FTLD, TDP-43, TTR, proteinopathy, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4. Of interest, transthyretin upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of transthyretin in frontal temporal lobar degeneration-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioural deficits. Thus, transthyretin conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that transthyretin is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.

Published
2023

5. TDP-43 proteinopathy impairs mRNP granule mediated postsynaptic translation and mRNA metabolism

Author

Wong, Chia-En, Jin, Lee-Way, Chu, Yuan-Ping, Wei, Wei-Yen, Ho, Pei-Chuan, and Tsai, Kuen-Jer

Subjects
Neurodegenerative, Genetics, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Animals, DNA-Binding Proteins, Dendrites, Disease Models, Animal, Disks Large Homolog 4 Protein, Frontotemporal Lobar Degeneration, Gene Expression Regulation, HEK293 Cells, Humans, Mice, Mice, Transgenic, Microscopy, Neuronal Plasticity, Neurons, Primary Cell Culture, Prosencephalon, Protein Biosynthesis, Protein Transport, RNA, Messenger, Ribonucleoproteins, Subcellular Fractions, Synapses, TDP-43 Proteinopathies, TDP-43, local translation, mRNP granule, postsynaptic, super-resolution microscopy, Oncology and Carcinogenesis
Abstract

Background: Local protein synthesis and mRNA metabolism mediated by mRNP granules in the dendrites and the postsynaptic compartment is essential for synaptic remodeling and plasticity in neuronal cells. Dysregulation of these processes caused by TDP-43 proteinopathy leads to neurodegenerative diseases, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Methods: Using biochemical analysis and imaging techniques, including super-resolution microscopy, we provide evidence, for the first time, for the postsynaptic localization of TDP-43 in mammalian synapses and we show that TDP-43 is a component of neuronal mRNP granules. Results: With activity stimulation and various molecular approaches, we further demonstrate activity-dependent mRNP granule dynamics involving disassembly of mRNP granules, release of mRNAs, activation of local protein translation, and the impairment of granule disassembly in cellular, animal and human models of TDP-43 proteinopathy. Conclusion: Our study elucidates the interplay between TDP-43 and neuronal mRNP granules in normal physiology and TDP-43 proteinopathy in the regulation of local protein translation and mRNA metabolism in the postsynaptic compartment.

Published
2021

6. HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP‐43 proteinopathies

Author

Wu, Cheng‐Chun, Jin, Lee‐Way, Wang, I‐Fang, Wei, Wei‐Yen, Ho, Pei‐Chuan, Liu, Yu‐Chih, and Tsai, Kuen‐Jer

Subjects
Neurodegenerative, Acquired Cognitive Impairment, Neurosciences, Genetics, Frontotemporal Dementia (FTD), Dementia, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amyotrophic Lateral Sclerosis, Animals, Cell Cycle, DNA Damage, DNA-Binding Proteins, Frontotemporal Lobar Degeneration, Histone Deacetylase 1, Humans, Mice, TDP-43 Proteinopathies, DNA damage, FTLD, HDAC1, TDP-43, Biological Sciences, Medical and Health Sciences
Abstract

TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.

Published
2020

17. Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP.

Author

Wang, Liang-Chao, Wang, Liang-Chao, Ho, Pei-Chuan, Wei, Wei-Yen, Tsai, Kuen-Jer, Chu, Yuan-Ping, Jin, Lee-Way, Wang, Liang-Chao, Wang, Liang-Chao, Ho, Pei-Chuan, Wei, Wei-Yen, Tsai, Kuen-Jer, Chu, Yuan-Ping, and Jin, Lee-Way

Abstract

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4. Of interest, transthyretin upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of transthyretin in frontal temporal lobar degeneration-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioural deficits. Thus, transthyretin conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that transthyretin is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.

Published
2023

19. TIMP3/Wnt Axis Regulates Gliosis of Müller Glia

Author

Hung, Jia-Horung, primary, Tsai, Ping-Hsing, additional, Aala, Wilson Jr F., additional, Chen, Chao-Chung, additional, Chiou, Shih-Hwa, additional, Wong, Tak-Wah, additional, Tsai, Kuen-Jer, additional, Hsu, Sheng-Min, additional, and Wu, Li-Wha, additional

Published
2023
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44. HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP-43 proteinopathies.

Author

Wu, Cheng-Chun, Wu, Cheng-Chun, Jin, Lee-Way, Wang, I-Fang, Wei, Wei-Yen, Ho, Pei-Chuan, Liu, Yu-Chih, Tsai, Kuen-Jer, Wu, Cheng-Chun, Wu, Cheng-Chun, Jin, Lee-Way, Wang, I-Fang, Wei, Wei-Yen, Ho, Pei-Chuan, Liu, Yu-Chih, and Tsai, Kuen-Jer

Abstract

TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.

Published
2020

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