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Prion-like Behavior in the Huntingtin Protein

Prion-Like Behavior in the Huntingtin Protein:

Protein aggregates are a hallmark feature of Huntington’s disease (HD)[1], as well as a number of other neurodegenerative diseases. These protein aggregates, composed of misfolded proteins that clump together, are traditionally thought to develop in vulnerable neurons individually. However, recent research suggests that these misfolded proteins may be transmitted from neuron to neuron.


Transmission of disease-causing proteins between cells is not new in the scientific literature. The idea of an infectious agent composed only of proteins, called prions, was first proposed in 1967[2], and is now known to cause a number of neurodegenerative diseases in animals and humans. Prions cause other proteins to fold into the wrong shape. Some research suggests that proteins demonstrating prion-like behavior may play a role in other neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Amyotrophic Lateral Sclerosis (ALS)[3]. This destructive process mainly appears in functioning, connected neural networks. Unlike prions, proteins involved in these neurodegenerative diseases are not infectious between individuals or species [4]. A study published in Nature in August 2014 by Pecho-Vrieseling et al. [5] suggests that the protein that creates protein aggregates in HD patients, mutant huntingtin (mHTT), may spread from cell to cell. This study provides valuable insight into what is currently understood about the role of protein aggregates and HD.

The study examines whether mHTT can spread among and propagate in vulnerable neurons using R6/2 HD mouse models and normal human stem cells. The researchers used genetically modified mice that express human mHTT fragments (only small portion of mHTT containing the polyglutamine stretch) and have accelerated HD-like pathophysiology. They began by implanting human neuronal progenitor cells without mHTT (derived from normal human stem cells), into HD mouse brain slices. The researchers determined that the human cells were successfully integrated in the brain slice as functional neurons. Then, they demonstrated that the healthy human cells were able to acquire aggregates of mouse mHTT protein and underwent similar changes as the sick mouse cells, including fewer projections from neurons and loss in medium spiny neurons.

Finally, in order to investigate if mHTT was transmitted from cell to cell via synapses, the researchers treated co-cultures of human neurons and HD mouse brain slices with a neurotoxin, botulinum toxin, which blocks vesicle fusion with the plasma membrane and prevents the neurons from releasing neurotransmitters. In the presence of this neurotoxin, the HD mouse neurons contained mHTT aggregates but the human cells did not. This evidence suggests that mHTT is transmitted along the cortical striatal pathway and is transmitted across neurons via synapses.
If mHTT is passed from neuron to neuron, it could have important implications on therapeutic interventions because the propagation can be experimentally blocked. In the past, neural transplants have been tested as a therapeutic for HD patients. If mHTT is indeed able to escape between cells, this could lead to a failure of neural transplants in HD patients. The biological mechanisms by which misfolding proteins are transmitted to functioning neural networks in this study are still unclear. The authors of the paper speculate that mHTT transfer depends on synaptic activity, and suggest that mHTT is transmitted at the synapse. However, much more research is still needed to determine whether this prion-like process actually affects human HD onset and/or progression.

This recent study adds to the understanding of the development of protein aggregates in HD by demonstrating that in certain lab conditions, mHTT can escape one cell and enter another. It is possible that cell-to cell propagation of mHTT may be another factor in the development of protein aggregates in HD. However, although this work is very well done and novel, it is unclear whether this process has any relevance to disease development. The role of protein aggregates in HD development is still widely debated.

[1]Arrasate, Montserrat and Steven Finkbeiner, “S. Protein aggregates in Huntington’s disease. Exp. Neurol. 2012, 238,:11-11.
[2] Griffith, J.S. “Nature of the Scrapie Agent: Self-replication and the Scrapie.” Nature 2 Sept. 1967: 1043-1044.
[3]Guo, Jing L. and Virginia M Y Lee. “Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases.” Nature Medicine (2014) 20: 130-138.
[4]Aguzzi et al. “Cell Biology: Beyond the prion principle.” Nature, 18 Jun. 2009, 459: 924-925.
[5]Pecho-Vrieseling et al. “Transneuronal propagation of mutant huntingtin
contributes to non-cell autonomous pathology in neurons.” Nature Neuroscience Aug. 2014; 1(8): 1064-1072.