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Mutant huntingtin is present in neuronal grafts in huntington disease patients
Author(s) -
Cicchetti Francesca,
Lacroix Steve,
Cisbani Giulia,
Vallières Nicolas,
SaintPierre Martine,
StAmour Isabelle,
Tolouei Ranna,
Skepper Jeremy N.,
Hauser Robert A.,
Mantovani Diego,
Barker Roger A.,
Freeman Thomas B.
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24174
Subject(s) - huntingtin , neuropil , huntingtin protein , biology , huntington's disease , mutant , pathology , central nervous system , epitope , extracellular matrix , extracellular , microbiology and biotechnology , neuroscience , antibody , immunology , disease , genetics , medicine , gene
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. Ann Neurol 2014;76:31–42