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Suzuki Y.,Tokyo Metropolitan Institute of Medical Science
Proceedings of the Japan Academy Series B: Physical and Biological Sciences | Year: 2014

Chaperone therapy is a newly developed molecular therapeutic approach to protein misfolding diseases. Among them we found unstable mutant enzyme proteins in a few lysosomal diseases, resulting in rapid intracellular degradation and loss of function. Active-site binding low molecular competitive inhibitors (chemical chaperones) paradoxically stabilized and enhanced the enzyme activity in somatic cells by correction of the misfolding of enzyme protein. They reached the brain through the blood-brain barrier after oral administration, and corrected pathophysiology of the disease. In addition to these inhibitory chaperones, non-competitive chaperones without inhibitory bioactivity are being developed. Furthermore molecular chaperone therapy utilizing the heat shock protein and other chaperone proteins induced by small molecules has been experimentally tried to handle abnormally accumulated proteins as a new approach particularly to neurodegenerative diseases. These three types of chaperones are promising candidates for various types of diseases, genetic or non-genetic, and neurological or nonneurological, in addition to lysosomal diseases. © 2014 The Japan Academy.

Uchihara T.,Tokyo Metropolitan Institute of Medical Science | Giasson B.I.,University of Florida
Acta Neuropathologica | Year: 2016

Progressive aggregation of alpha-synuclein (αS) through formation of amorphous pale bodies to mature Lewy bodies or in neuronal processes as Lewy neurites may be the consequence of conformational protein changes and accumulations, which structurally represents “molecular template”. Focal initiation and subsequent spread along anatomically connected structures embody “structural template”. To investigate the hypothesis that both processes might be closely associated and involved in the progression of αS pathology, which can be observed in human brains, αS amyloidogenic precursors termed “seeds” were experimentally injected into the brain or peripheral nervous system of animals. Although these studies showed that αS amyloidogenic seeds can induce αS pathology, which can spread in the nervous system, the findings are still not unequivocal in demonstrating predominant transsynaptic or intraneuronal spreads either in anterograde or retrograde directions. Interpretation of some of these studies is further complicated by other concurrent aberrant processes including neuroimmune activation, injury responses and/or general perturbation of proteostasis. In human brain, αS deposition and neuronal degeneration are accentuated in distal axon/synapse. Hyperbranching of axons is an anatomical commonality of Lewy-prone systems, providing a structural basis for abundance in distal axons and synaptic terminals. This neuroanatomical feature also can contribute to such distal accentuation of vulnerability in neuronal demise and the formation of αS inclusion pathology. Although retrograde progression of αS aggregation in hyperbranching axons may be a consistent feature of Lewy pathology, the regional distribution and gradient of Lewy pathology are not necessarily compatible with a predictable pattern such as upward progression from lower brainstem to cerebral cortex. Furthermore, “focal Lewy body disease” with the specific isolated involvement of autonomic, olfactory or cardiac systems suggests that spread of αS pathology is not always consistent. In many instances, the regional variability of Lewy pathology in human brain cannot be explained by a unified hypothesis such as transsynaptic spread. Thus, the distribution of Lewy pathology in human brain may be better explained by variable combinations of independent focal Lewy pathology to generate “multifocal Lewy body disease” that could be coupled with selective but variable neuroanatomical spread of αS pathology. More flexible models are warranted to take into account the relative propensity to develop Lewy pathology in different Lewy-prone systems, even without interconnections, compatible with the expanding clinicopathological spectra of Lewy-related disorders. These revised models are useful to better understand the mechanisms underlying the variable progression of Lewy body diseases so that diagnostic and therapeutic strategies are improved. © 2015, The Author(s).

Mizushima N.,Tokyo Medical and Dental University | Komatsu M.,Tokyo Metropolitan Institute of Medical Science
Cell | Year: 2011

Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy's role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease. © 2011 Elsevier Inc.

Komatsu M.,Tokyo Metropolitan Institute of Medical Science
Journal of Biochemistry | Year: 2012

Autophagy has long been thought of as a bulk degradation system in which cytoplasmic components are sequestered by double-membrane structures called autophagosomes, and the contents are then degraded after autophagosomes fuse with lysosomes. Genetic experiments in yeast identified a set of Autophagy-related (ATG) genes that are essential for autophagy. We have since elucidated many of the molecular underpinnings of autophagy and the physiologic roles of these processes in various systems. This review summarizes the physiologic roles of autophagy with a particular focus on liver autophagy based on analyses of knockout mice lacking Atg genes. The Authors 2012. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved2012 © The Authors 2012. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Tatsumi K.,Tokyo Metropolitan Institute of Medical Science
Nature communications | Year: 2011

Post-translational protein modifications are systems designed to expand restricted genomic information through functional conversion of target molecules. Ubiquitin-like post-translational modifiers regulate numerous cellular events through their covalent linkages to target protein(s) by an enzymatic cascade analogous to ubiquitylation consisting of E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development. Mice lacking Uba5 exhibited severe anaemia, followed by death in utero. Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors. Intriguingly, transgenic expression of Uba5 in the erythroid lineage rescued the Uba5-deficient embryos from anaemia and prolonged their survival, demonstrating the importance of Uba5 in cell-autonomous erythroid differentiation. Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis.

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