Editors' ChoiceHuntington’s Disease

Toxic Proteins on the Move

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Science Translational Medicine  20 Aug 2014:
Vol. 6, Issue 250, pp. 250ec144
DOI: 10.1126/scitranslmed.3010125

The spread of toxic protein aggregates from cell to cell in the brain has recently been implicated in several neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Two recent studies—one in mice and the other in human tissues—suggest that extracellular spread and aggregation of mutant huntingtin protein occurs in Huntington’s disease (HD), a devastating neurodegenerative disorder characterized by a trinucleotide repeat in the gene Huntingtin. Neurotoxicity of CAG-expanded Huntingtin has long been thought to be a cell-autonomous process, with mutant huntingtin protein exerting damage only to the cells that express it. Pecho-Vrieseling et al. now demonstrate that when wild-type human stem cell–derived neurons incorporate into brain slices from mutant huntingtin-expressing transgenic mice, huntingtin aggregates began to appear in the normal cells, suggesting transcellular spread. Using mixed slice cultures containing wild-type and huntingtin-expressing cells, the authors demonstrated that the huntingtin aggregates spread from neuron to neuron via a mechanism requiring synaptic transmission. Moreover, the spread of these aggregates into wild-type neurons appears to cause cell toxicity.

In accordance with the findings of Pecho-Vrieseling et al., in a study earlier this year Cicchetti and colleagues provided similar evidence that extracellular spread and aggregation of huntngtin occurs in the human brain. They examined post mortem tissue from four HD patients who received striatal stem cell grafts years before death. Although the grafts were from unrelated donors without HD, the authors identified abundant extracellular huntingtin aggregates throughout the grafted tissue. Because aggregation of huntingtin is not observed in non-HD brain, the authors conclude that mutant huntingtin must have spread from the affected brain into the extracellular space, then into the grafted tissue. It is unclear whether huntingtin invades the grafted tissue in a soluble form then aggregates, or whether aggregates themselves spread. Furthermore, the extracellular huntingtin aggregates described by Cicchetti et al. may be distinct from the intracellular aggregates observed by Pecho-Vrieseling and colleagues.

These two studies implicate cell-to-cell huntingtin spread in HD pathogenesis and suggest that antibody-based therapies targeting extracellular huntingtin might be effective. These findings also reveal a potential pitfall for transplant-based therapies for HD. Although it is still unknown how huntingtin spreads or how this spreading contributes to the pathophysiology of HD in humans, these studies have important therapeutic implications for the treatment of this devastating disease.

E. Pecho-Vrieseling et al., Transneuronal propagation of mutant huntingtin contributes to non–cell autonomous pathology in neurons. Nat. Neurosci. 17, 1064–1072 (2014). [Abstract]

F. Cicchetti et al., Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann. Neurol. 76, 31–42 (2014). [Abstract]

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