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S4‐02‐01: Can the mutant huntingtin gene product spread from cell to cell? Evidence from neuronal allografts in huntington's disease patients
Author(s) -
Cicchetti Francesca
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.325
Subject(s) - huntingtin , neuropil , biology , huntingtin protein , huntington's disease , extracellular matrix , cell , microbiology and biotechnology , extracellular , mutant , epitope , antibody , gene , pathology , immunology , disease , neuroscience , genetics , central nervous system , medicine
Huntington’s 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 where degeneration occurs within individual cells that carry the aberrant gene. Here, we investigated the hypothesis that mHtt (like pathogenic protein species involved in other neurodegenerative conditions) is capable of spreading within cerebral tissue.The brains of four patients with HD who received genetically unrelated fetal neural allografts at least a decade earlier were examined post-mortem. The presence of mHtt aggregates within the grafted tissue was confirmed using an array of techniques including microscopy (brightfield, fluorescence and electron), western immunoblotting and infrared spectroscopy, and a number of different antibodies targeting different epitopes of mHtt aggregates.A number of mHtt protein aggregates were located within intracerebral allografts of striatal tissue in three of these HD patients. No grafts survived in the fourth transplant recipient. The mHtt+ aggregates were observed in the extracellular matrix of the genetically unrelated transplanted tissue while in the host brain they were localized in neurons, neuropil, extracellular matrix and blood vessels. In addition, peripheral immune cells in separate HD patients contained mHtt. There are a thus a number of non cell-autonomous mechanisms which could explain these observations including transynaptic propagation as well as hematogenous transport of mHtt, among others.In summary, we have shown, for the first time, the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brains of HD patients. These observations raise questions on the importance of non-cell autonomous mechanisms of protein spread in genetic disorders of the CNS, and further provide new targets for the development of therapeutic strategies.Supported by the International Organization of Glutaric Acidemia (IOGA) awarded to FC who is also recipient of a National Researcher career award from FRQS. Disclosure: Dr. Cicchetti has nothing to disclose. Dr. Lacroix has nothing to disclose. Dr. Cisbani has nothing to disclose. Dr. Vallieres has nothing to disclose. Dr. Saint-Pierre has nothing to disclose. Dr. St-Amour has nothing to disclose. Dr. Tolouei has nothing to disclose. Dr. Skepper has nothing to disclose. Dr. Hauser has received personal compensation for activities with Abbott Laboratories, Allergan, Inc., Abbvie, AstraZeneca, Biotie Therapies, Chelsea Therapeutics, Eli Lilly, GE Healthcare, Impax Laboratories, and Ipsen Biopharmaceuticals. Dr. Mantovani has nothing to disclose. Dr. Barker has received personal compensation for activities with Solvay Healthcare, Teva Pharmaceuticals, DanioLabs, Synosia Therapeutics. Dr. Freeman has nothing to disclose.