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Mutant huntingtin is present in neuronal grafts in Huntington disease patients

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. Ann Neurol. 2014;76(1):31-42.

Centre Hospitalier Universitaire de Québec Research Center; Departments of Psychiatry and Neurosciences.

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 mutant huntingtin is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing Huntington disease.

METHODS:

The presence of mutant huntingtin 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 mutant huntingtin aggregates.

RESULTS:

We describe the presence of mutant huntingtin aggregates within intracerebral allografts of striatal tissue in 3 Huntington disease patients who received their transplants approximately 1 decade earlier and then died secondary to the progression of their disease. The mutant huntingtin(+) 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 mutant huntingtin in genetically normal and unrelated allografted neural tissue transplanted into the brain of affected Huntington disease 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.

© 2014 American Neurological Association.

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Mutant huntingtin is present in neuronal grafts in Huntington disease patients - Global Medical Discovery