Mutant huntingtin is present in neuronal grafts in huntington disease patients
Corresponding Author
Francesca Cicchetti PhD
Centre Hospitalier Universitaire de Québec Research Center
Departments of Psychiatry and Neurosciences
Address correspondence to Dr Cicchetti, Centre Hospitalier Universitaire de Quebec Research Center, Axe Neurosciences, T2-50, 2705, Boulevard Laurier, Québec, QC, G1V 4G2, Canada. E-mail: [email protected]Search for more papers by this authorSteve Lacroix PhD
Centre Hospitalier Universitaire de Québec Research Center
Molecular Medicine, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorGiulia Cisbani MSc
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorNicolas Vallières MSc
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorMartine Saint-Pierre DEC
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorIsabelle St-Amour PhD
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorRanna Tolouei PhD
Biomaterials and Bioengineering Laboratory, Saint-François d'Assise Hospital
Department of Mining Engineering, Metallurgy, and Materials, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorJeremy N. Skepper PhD
Cambridge Advanced Imaging Centre, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorRobert A. Hauser MD
Departments of Neurology, Pharmacology, and Experimental Therapeutics, Parkinson's Disease and Movement Disorders National Parkinson's Foundation Center of Excellence, University of South Florida, Tampa, Florida
Search for more papers by this authorDiego Mantovani PhD
Biomaterials and Bioengineering Laboratory, Saint-François d'Assise Hospital
Department of Mining Engineering, Metallurgy, and Materials, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorRoger A. Barker MD, PhD
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorThomas B. Freeman MD
Department of Neurosurgery and Brain Repair
Center of Excellence for Aging and Brain Repair, University of South Florida, Tampa, Florida
Search for more papers by this authorCorresponding Author
Francesca Cicchetti PhD
Centre Hospitalier Universitaire de Québec Research Center
Departments of Psychiatry and Neurosciences
Address correspondence to Dr Cicchetti, Centre Hospitalier Universitaire de Quebec Research Center, Axe Neurosciences, T2-50, 2705, Boulevard Laurier, Québec, QC, G1V 4G2, Canada. E-mail: [email protected]Search for more papers by this authorSteve Lacroix PhD
Centre Hospitalier Universitaire de Québec Research Center
Molecular Medicine, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorGiulia Cisbani MSc
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorNicolas Vallières MSc
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorMartine Saint-Pierre DEC
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorIsabelle St-Amour PhD
Centre Hospitalier Universitaire de Québec Research Center
Search for more papers by this authorRanna Tolouei PhD
Biomaterials and Bioengineering Laboratory, Saint-François d'Assise Hospital
Department of Mining Engineering, Metallurgy, and Materials, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorJeremy N. Skepper PhD
Cambridge Advanced Imaging Centre, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorRobert A. Hauser MD
Departments of Neurology, Pharmacology, and Experimental Therapeutics, Parkinson's Disease and Movement Disorders National Parkinson's Foundation Center of Excellence, University of South Florida, Tampa, Florida
Search for more papers by this authorDiego Mantovani PhD
Biomaterials and Bioengineering Laboratory, Saint-François d'Assise Hospital
Department of Mining Engineering, Metallurgy, and Materials, Laval University, Quebec City, Quebec, Canada
Search for more papers by this authorRoger A. Barker MD, PhD
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorThomas B. Freeman MD
Department of Neurosurgery and Brain Repair
Center of Excellence for Aging and Brain Repair, University of South Florida, Tampa, Florida
Search for more papers by this authorAbstract
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
Supporting Information
Additional Supporting Information can be found in the online version of this article.
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