New Prion Research Focuses Attention on the UPR in Huntington’s Disease

Researchers at the University of Leicester have learned some insight from studying prion disease that they believe may lead to therapeutic targets in other neurodegenerative disorders.

Prion diseases, which are currently untreatable, are caused by an infectious protein entering into the cells or neurons and causing the proteins in the cell to misfold. These misfolded proteins also infect other proteins.  As the disease progresses, more and more prion protein accumulates in the cell, causing cell death and eventually death of the person or animal.  There are a number of prion diseases.  Perhaps best known is ‘mad cow’ disease, Bovine spongiform encephalopathy, which humans can acquire by eating the meat of infected cows.  A similar human prion disease is Creutzfeldt–Jakob disease.

Working with an animal model of prion disease, the researchers explored the course of the disease.  They found that replication of the prion protein triggers the unfolded protein response (UPR).  One arm of the UPR upregulates chaperones to bring about refolding.  The other arm reduces protein synthesis to allow the cell to deal with the misfolded protein.  In this pathway, eIF2a, the a-subunit of the eukaryotic translation initiation factor, is phosphorylized, The phosphorylation interferes with the translation of the instructions to make new proteins.

While the activation of the UPR and transient eIF2a phosphorylation helps cells which are overloaded with misfolded protein by reducing protein synthesis and increasing chaperones to bring about refolding to allow the cell to handle the misfolded protein buildup, when phosphorylation of eIF2a persists, it becomes dysfunctional.  The continuing shutdown of protein synthesis deprives the cell of the proteins it needs.  Most critical is the loss of synaptic proteins; this triggers cell death.  Persistence of this arm of the UPR is part of the pathology of prion disease.

The researchers found that they could increase survival time in the mice by overexpressing  GADD34, a eIF2a-P phosphatase, as well as by reducing of levels of prion protein through RNA interference.  Both approaches reduced eIF2a-P levels and restored vital translation rates, rescued synaptic deficits, and reduced neuronal loss.  The results suggest that a promising therapeutic strategy for prion diseases would be manipulation of translational control.

Professor Giovanna Mallucci, who led the team, said, "What's exciting is the emergence of a common mechanism of brain cell death, across a range of different neurodegenerative disorders, activated by the different mis-folded proteins in each disease. The fact that, in mice with prion disease, we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders. Instead of targeting individual mis-folded proteins in different neurodegenerative diseases, we may be able to target the shared pathways and rescue brain cell degeneration irrespective of the underlying disease."

The press release suggesting that the insights from the exploration of the role of the UPC in prion disease might have relevance for other neurological diseases with misfolded proteins such as Huntington’s disease has interested the HD community.  Is the unfolded protein response activated in Huntington’s disease?  If so, does it cause pathology and of what nature?

Researchers in Chile conducted a review of the literature on the role of ER (endoplasmic reticulum) stress and Huntington’s disease.  The ER is involved in the folding of proteins and the transport of synthesized proteins..  Only if a protein is folded correctly will it be transported to its final destination.  Abnormal accumulation of unfolded proteins causes ER stress.  As with prion and other neurodegenerative diseases, the UPR is activated in Huntington’s disease.  The UPR orchestrates adaptive responses to ER, one of which is the phosphorylation of eIF2a but this has not yet been explored as a potential problem area as it is in prion disease.   However, there are a variety of problems associated with ER stress that are found in HD, including inhibition of protein degradation in the ER, altered vesicular trafficking and axonal transport, disrupted autophagy, and impaired calcium homeostasis.

These same researchers plus additional colleagues have recently shown that targeting a UPR transcription factor, X-box binding protein 1 (XPB1), for reduction in an HD mouse model resulted in a drastic decrease in levels of the mutant HD protein, reduced symptomology and improved neuronal survival.   Since the reduction of XBP1 led to an enhanced expression of Forkhead box O1 (FoxO1), a key transcription factor regulating autophagy in neurons, the researchers hypothesize that upregulated autophagy was responsible for the improvement.  In contrast, targeting a different UPR transcription factor, ATF4, did not result in improvement.

To examine whether UPR activation is a factor in Huntington’s disease progression, another team of researchers from Portugal analyzed gene expression data in mouse models and human patients. They found that genes associated with ER stress and UPR activation are regulated during the early stages of HD.

The research to date seems to show that researching the unfolded protein response may lead to therapeutic targets in Huntington’s Disease as it did in prion disease although these targets may not be the same.  Research in other neurodegenerative diseases can provide insight for HD researchers and vice versa.


Ravi Kiran Reddy Kalathur, KameshwarAyasolla and Matthias E. Futschik. The Unfolded Protein Response and its potential role in Huntington´s disease.’ Nature Proceedings 2012

*Julie A. Moreno, Helois Radford, Diego Peretti, Joern R. Steinert, Nicholas Verity, Maria Guerra Martin, Mark Halliday, Jason Morgan, David Dinsdale1, Catherine A. Ortori, David A. Barrett, Pavel Tsaytler, Anne Bertolotti, Anne E.Willis, Martin Bushell, & Giovanna R. Mallucci.  “Sustained translational repression by eIF2a-P mediates prion neurodegeneration.” Nature 2012.

Rene L. Vidal, Alicia Figueroa, Fekuoe A. Court, Peter Thielen, Claudia Molina, Craig Wirth, Benjamen Caballero, Robert Kiffin, Juan Segura-Aguilar, Ana Maria Cuervo, Laurie H. Glimcher, and Claudio Hetz.  “Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy.” Molecular Genetics 2012 May 15;21(10):2245-62.

R. Vidal, B. Caballero, A. Couv2 and C. Hetz. “Converging Pathways in the Occurrence of Endoplasmic Reticulum (ER) Stress in Huntington’s Disease.” Current Molecular Medicine 2011 Feb;11(1):1-12.

- Marsha L. Miller, Ph.D., May 25, 2012