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Mutant huntingtin is present in neuronal grafts in huntington disease patients
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 pro…
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“Furthermore, mutant huntingtin aggregates accumulate in brain endothelial cells, perivascular macrophages, SMCs, and vascular basal lamina in HD (155), and in genetically unrelated neural allografts within the brains of patients with advanced HD (114), suggesting that cerebral vasculature may contribute spreading of mutant huntingtin.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [114]
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Metadata
- Authors
- Cicchetti, F., Lacroix, S., Cisbani, G., Vallières, N., Saint‐Pierre, M., St‐Amour, I., Tolouei, R., Skepper, J. N., Hauser, R. A., Mantovani, D., Barker, R. A., & Freeman, T. B.
- Affiliations
- Centre hospitalier universitaire de Québec (CA)
- Hôpital Saint-François d'Assise (CA)
- University of Cambridge (GB)
- University of South Florida (US)
- Corresponding author
- Cicchetti, Francesca
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2014-06-06
- Volume
- 76
- Issue
- 1
- Pages
- 31-42
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2148853271
- Cited by
- 193
- References
- 49
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 10 · 2023: 15 · 2022: 18 · 2021: 18 · 2020: 21 · 2019: 12 · 2018: 23 · 2017: 21 · 2016: 12 · 2015: 19 · 2014: 8
- FWCI
- 9.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- International Organization of Glutaric Acidemia (IOGA)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- mutant huntingtin, protein aggregation, striatal transplantation, extracellular matrix
- MeSH terms
- Huntingtin Protein, Adult, Clinical Trials as Topic, Humans, Huntington Disease, Middle Aged, Mutation, Nerve Tissue Proteins, Fetal Tissue Transplantation, Brain Tissue Transplantation, Neostriatum, Allografts
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