title: Human-to-mouse prion-like propagation of mutant huntingtin protein.
abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell-autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and healthy host tissue following implantation into the cerebral ventricles of neonatal mice in a non-cell-autonomous fashion. Transmitted mHtt aggregates gave rise to both motor and cognitive impairments, loss of striatal medium spiny neurons, increased inflammation and gliosis in associated brain regions, thereby recapitulating the behavioural and pathological phenotypes which characterizes HD. In addition, both in vitro work using co-cultures of mouse neural stem cells with 143 CAG fibroblasts and the SH-SY5Y human neuroblastoma cell line as well as in vivo experiments conducted in newborn wild-type mice suggest that exosomes can cargo mHtt between cells triggering the manifestation of HD-related behaviour and pathology. This is the first evidence of human-to-mouse prion-like propagation of mHtt in the mammalian brain; a finding which will help unravel the molecular bases of HD pathology as well as to lead to the development of a whole new range of therapies for neurodegenerative diseases of the CNS.
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Iksoo
authors.initials: I
authors.lastname: Jeon
authors.affiliation: Centre de recherche du CHU de Québec (CHUQ), Québec, QC, G1V 4G2, Canada.|Département de Psychiatrie and Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cicchetti
authors.affiliation: Centre de recherche du CHU de Québec (CHUQ), Québec, QC, G1V 4G2, Canada.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cisbani
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Suji
authors.initials: S
authors.lastname: Lee
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Endan
authors.initials: E
authors.lastname: Li
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Jiwoo
authors.initials: J
authors.lastname: Bae
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Nayeon
authors.initials: N
authors.lastname: Lee
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Wooseok
authors.initials: W
authors.lastname: Im
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Kim
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Seung-Hun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Tae-Aug
authors.initials: TA
authors.lastname: Kim
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
authors.forename: Jung Jae
authors.initials: JJ
authors.lastname: Ko
authors.affiliation: Centre de recherche du CHU de Québec (CHUQ), Québec, QC, G1V 4G2, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Aubé
authors.affiliation: Centre de recherche du CHU de Québec (CHUQ), Québec, QC, G1V 4G2, Canada.|Département de Médecine Moléculaire, Université Laval, Québec, QC, G1V 0A6, Canada.
authors.forename: Abid
authors.initials: A
authors.lastname: Oueslati
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Korea.
authors.forename: Yun Joong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: CHA Stem Cell Institute, CHA University, Room 604, CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea. jsong@cha.ac.kr.
authors.forename: Jihwan
authors.initials: J
authors.lastname: Song
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000473:pathology; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000473:pathology
chemical_list: D000071058:Huntingtin Protein; D050505:Mutant Proteins
keywords: Exosomes; Full-length mutant huntingtin; Human fibroblasts; Human-induced pluripotent stem cells; Huntington’s disease