Advanced

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 and Mantovani, Diego, et al. (2014) In Annals of Neurology 76(1). p.31-42
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
publishing date
type
Contribution to journal
publication status
published
keywords
Adult, Allografts, Brain Tissue Transplantation, Clinical Trials as Topic, Fetal Tissue Transplantation, Humans, Huntington Disease, Middle Aged, Mutation, Neostriatum, Nerve Tissue Proteins, Journal Article, Research Support, Non-U.S. Gov't
in
Annals of Neurology
volume
76
issue
1
pages
12 pages
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:84904787076
ISSN
1531-8249
DOI
10.1002/ana.24174
language
English
LU publication?
no
id
a2db8865-c5f9-4617-b1b0-784739d540c8
date added to LUP
2016-11-24 15:09:07
date last changed
2017-11-12 04:26:27
@article{a2db8865-c5f9-4617-b1b0-784739d540c8,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Cicchetti, Francesca and Lacroix, Steve and Cisbani, Giulia and Vallières, Nicolas and Saint-Pierre, Martine and St-Amour, Isabelle and Tolouei, Ranna and Skepper, Jeremy N and Hauser, Robert A and Mantovani, Diego and Barker, Roger A and Freeman, Thomas B},
  issn         = {1531-8249},
  keyword      = {Adult,Allografts,Brain Tissue Transplantation,Clinical Trials as Topic,Fetal Tissue Transplantation,Humans,Huntington Disease,Middle Aged,Mutation,Neostriatum,Nerve Tissue Proteins,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {31--42},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Mutant huntingtin is present in neuronal grafts in Huntington disease patients},
  url          = {http://dx.doi.org/10.1002/ana.24174},
  volume       = {76},
  year         = {2014},
}