@article{214b37392a5445d7b70d6ce8b3386834,
title = "Expression of Mutant Ubiquitin and Proteostasis Impairment in Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex Brains",
abstract = "Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder that is endemic to the Kii peninsula of Japan. The disorder is clinically characterized by a variable combination of parkinsonism, dementia, and motor neuron symptoms. Despite extensive investigations, the etiology and pathogenesis of ALS/PDC remain unclear. At the neuropathological level, Kii ALS/PDC is characterized by neuronal loss and tau-dominant polyproteinopathy. Here, we report the accumulation of several proteins involved in protein homeostasis pathways, that is, the ubiquitin-proteasome system and the autophagylysosome pathway, in postmortem brain tissue from a number of Ku ALS/PDC cases (n = 4). Of particular interest is the presence of a mutant ubiquitin protein (UBB+1), which is indicative of disrupted ubiquitin homeostasis. The findings suggest that abnormal protein aggregation is linked to impaired protein homeostasis pathways in Kii ALS/PDC.",
keywords = "Autophagy, Kii ALS/PDC, Protein aggregation, Protein quality control, Tauopathy, UBB+1, Ubiquitin-proteasome system, Unfolded protein response, NEURODEGENERATIVE DISORDERS, ENDEMIC DISEASE, PARKINSONISM, SCLEROSIS, TAU, ACCUMULATION, PENINSULA, PROTEIN, JAPAN, ALZHEIMERS",
author = "Verheijen, {Bert M.} and Satoru Morimoto and Ryogen Sasaki and Kiyomitsu Oyanagi and Yasumasa Kokubo and Shigeki Kuzuhara and {van Leeuwen}, {Fred W.}",
note = "Funding Information: This work was partly supported by grants-in-aid from the Mie Medical Fund (to SM and YK), Japan Intractable Diseases (Nanbyo) Research Foundation (to SM), Japan Foundation for Neuroscience and Mental Health (to YK), the Research Committee of CNS Degenerative Diseases (to YK, H29-Nanchi-Ippan-085, collaborator, 2017-2019), and the Research Committee of Muro Disease (Kii ALS/PDC) (to YK, 21210301, Chair, 2009-2014), by the Ministry of Health, Labor and Welfare (MHLW), Japan, through a grant-in-aid for the Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT; to YK, 25305030, Chair, 2013-2017, 18KK0239, Chair, 2018-2022, 17H01689, collaborator, 2017-2021, 18K07368, Chair, 2018-2020, to SM, 15J03921, Chair, 2015-2018, 19K17002, Chair, 2019-, to SK, 15K09634: Chair, 2015-2018, 18K07514: Chair, 2018-), the Collaborative Research Project of Brain Research Institute, Niigata University (to KO, 2907 and 201913), and by a grant-in-aid of the Research Consortium of Kii ALS/PDC from the Japan Agency for Medical Research and Development, AMED (to YK, 17ek0109139h0003, Chair, 2015-2017). We would like to thank Dr P. Davies (Albert Einstein College of Medicine) for his generous gift of MC1 and CP13 antibodies and Dr A. Iwata (Stanford University) for kindly providing the antibodies against ATG8 and ATG12. We thank collaborators of the Kii ALS/PDC research consortium and Dr B. Fisser, Dr R.A. Balesar, and Dr D.F. Swaab (Netherlands Institute for Neuroscience, The Netherlands) for assistance. We thank Dr M.H. Glickman (Technion, Israel) for discussing UBB{\th}1-DUB interaction data. Publisher Copyright: {\textcopyright} 2020 American Association of Neuropathologists, Inc.",
year = "2020",
month = aug,
doi = "10.1093/jnen/nlaa056",
language = "English",
volume = "79",
pages = "902--907",
journal = "Journal of Neuropathology and Experimental Neurology",
issn = "0022-3069",
publisher = "Oxford University Press",
number = "8",
}