Mutant huntingtin is present in neuronal grafts in Huntington disease patients

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Francesca Cicchetti
  • Steve Lacroix
  • Giulia Cisbani
  • Nicolas Vallières
  • Martine Saint-Pierre
  • Isabelle St-Amour
  • Ranna Tolouei
  • Jeremy N Skepper
  • Robert A Hauser
  • Diego Mantovani
  • Roger A Barker
  • Thomas B Freeman
Organisations
External organisations
  • University of Cambridge
Research areas and keywords

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
Original languageEnglish
Pages (from-to)31-42
Number of pages12
JournalAnnals of Neurology
Volume76
Issue number1
Publication statusPublished - 2014 Jul
Publication categoryResearch
Peer-reviewedYes