Mutant huntingtin is present in neuronal grafts in Huntington disease patients

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Mutant huntingtin is present in neuronal grafts in Huntington disease patients. / Cicchetti, Francesca; Lacroix, Steve; Cisbani, Giulia; Vallières, Nicolas; Saint-Pierre, Martine; St-Amour, Isabelle; Tolouei, Ranna; Skepper, Jeremy N; Hauser, Robert A; Mantovani, Diego; Barker, Roger A; Freeman, Thomas B.

In: Annals of Neurology, Vol. 76, No. 1, 07.2014, p. 31-42.

Research output: Contribution to journalArticle

Harvard

Cicchetti, F, Lacroix, S, Cisbani, G, Vallières, N, Saint-Pierre, M, St-Amour, I, Tolouei, R, Skepper, JN, Hauser, RA, Mantovani, D, Barker, RA & Freeman, TB 2014, 'Mutant huntingtin is present in neuronal grafts in Huntington disease patients', Annals of Neurology, vol. 76, no. 1, pp. 31-42. https://doi.org/10.1002/ana.24174

APA

Cicchetti, F., Lacroix, S., Cisbani, G., Vallières, N., Saint-Pierre, M., St-Amour, I., ... Freeman, T. B. (2014). Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Annals of Neurology, 76(1), 31-42. https://doi.org/10.1002/ana.24174

CBE

Cicchetti F, Lacroix S, Cisbani G, Vallières N, Saint-Pierre M, St-Amour I, Tolouei R, Skepper JN, Hauser RA, Mantovani D, Barker RA, Freeman TB. 2014. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Annals of Neurology. 76(1):31-42. https://doi.org/10.1002/ana.24174

MLA

Vancouver

Cicchetti F, Lacroix S, Cisbani G, Vallières N, Saint-Pierre M, St-Amour I et al. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Annals of Neurology. 2014 Jul;76(1):31-42. https://doi.org/10.1002/ana.24174

Author

Cicchetti, Francesca ; Lacroix, Steve ; Cisbani, Giulia ; Vallières, Nicolas ; Saint-Pierre, Martine ; St-Amour, Isabelle ; Tolouei, Ranna ; Skepper, Jeremy N ; Hauser, Robert A ; Mantovani, Diego ; Barker, Roger A ; Freeman, Thomas B. / Mutant huntingtin is present in neuronal grafts in Huntington disease patients. In: Annals of Neurology. 2014 ; Vol. 76, No. 1. pp. 31-42.

RIS

TY - JOUR

T1 - Mutant huntingtin is present in neuronal grafts in Huntington disease patients

AU - Cicchetti, Francesca

AU - Lacroix, Steve

AU - Cisbani, Giulia

AU - Vallières, Nicolas

AU - Saint-Pierre, Martine

AU - St-Amour, Isabelle

AU - Tolouei, Ranna

AU - Skepper, Jeremy N

AU - Hauser, Robert A

AU - Mantovani, Diego

AU - Barker, Roger A

AU - Freeman, Thomas B

N1 - © 2014 American Neurological Association.

PY - 2014/7

Y1 - 2014/7

N2 - OBJECTIVE: Huntington disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin [mHtt]), which is thought to exert its effects in a cell-autonomous manner. Here, we tested the hypothesis that mHtt is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing HD.METHODS: The presence of mHtt aggregates within the grafted tissue was confirmed using 3 different types of microscopy (bright-field, fluorescence, and electron), 2 additional techniques consisting of Western immunoblotting and infrared spectroscopy, and 4 distinct antibodies targeting different epitopes of mHtt aggregates.RESULTS: We describe the presence of mHtt aggregates within intracerebral allografts of striatal tissue in 3 HD patients who received their transplants approximately 1 decade earlier and then died secondary to the progression of their disease. The mHtt(+) aggregates were observed in the extracellular matrix of the transplanted tissue, whereas in the host brain they were seen in neurons, neuropil, extracellular matrix, and blood vessels.INTERPRETATION: This is the first demonstration of the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brain of affected HD patients. These observations raise questions on protein spread in monogenic neurodegenerative disorders of the central nervous system characterized by the formation of mutant protein oligomers/aggregates.

AB - OBJECTIVE: Huntington disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin [mHtt]), which is thought to exert its effects in a cell-autonomous manner. Here, we tested the hypothesis that mHtt is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing HD.METHODS: The presence of mHtt aggregates within the grafted tissue was confirmed using 3 different types of microscopy (bright-field, fluorescence, and electron), 2 additional techniques consisting of Western immunoblotting and infrared spectroscopy, and 4 distinct antibodies targeting different epitopes of mHtt aggregates.RESULTS: We describe the presence of mHtt aggregates within intracerebral allografts of striatal tissue in 3 HD patients who received their transplants approximately 1 decade earlier and then died secondary to the progression of their disease. The mHtt(+) aggregates were observed in the extracellular matrix of the transplanted tissue, whereas in the host brain they were seen in neurons, neuropil, extracellular matrix, and blood vessels.INTERPRETATION: This is the first demonstration of the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brain of affected HD patients. These observations raise questions on protein spread in monogenic neurodegenerative disorders of the central nervous system characterized by the formation of mutant protein oligomers/aggregates.

KW - Adult

KW - Allografts

KW - Brain Tissue Transplantation

KW - Clinical Trials as Topic

KW - Fetal Tissue Transplantation

KW - Humans

KW - Huntington Disease

KW - Middle Aged

KW - Mutation

KW - Neostriatum

KW - Nerve Tissue Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/ana.24174

DO - 10.1002/ana.24174

M3 - Article

VL - 76

SP - 31

EP - 42

JO - Annals of Neurology

JF - Annals of Neurology

SN - 1531-8249

IS - 1

ER -