Unfolding Neurodegenerative Disease Research

John C. Reed, MD, PhD

|Disclosures|May 31, 2012
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Hi, I'm Dr. John Reed of the Sanford-Burnham Medical Research Institute. I'm here today to comment on a recent publication that appeared in the journal Nature about mechanisms of neurodegeneration.[1]

Collectively, neurodegenerative diseases represent the third leading cause of death in America and most other developed nations. We are all alarmed about the rising rates of Alzheimer and Parkinson diseases associated with our aging population, and it's abundantly clear that the medicines we have currently for combating neurodegenerative diseases are inadequate -- most merely mask symptoms by replacing neurotransmitters rather than modifying the underlying disease mechanisms.

Essentially all neurodegenerative diseases involve protein misfolding. Whether it's amyloid in Alzheimer disease, alpha-synuclein in Parkinson disease, or the huntingtin protein in Huntington disease -- these disorders all involve the accumulation of misfolded proteins.

A recent report in Nature[1] described studies of mice that were engineered to express prions in their neurons. Prions are a class of proteins that cause encephalopathy in the context of mad cow disease and similar disorders. These proteins have been used experimentally as a model for studies of the consequences of protein unfolding in the brain.

The recent publication showed that accumulation of misfolded prions stimulated a cellular stress response called the "unfolded protein response.'" The molecular and cellular biology is complicated, but signals produced within the stressed cells cause a halt to protein synthesis. The proximal consequences of the cessation of protein synthesis seem to be loss of synaptic connections in the brain, followed later by neuronal cell death.

A key regulator of this cell stress response was identified as GADD34, a protein phosphatase. The investigators introduced into the brains of prion-infected mice recombinant viruses engineered to produce this phosphatase GADD34, which restored protein synthesis, preserved synapses, and reduced neuronal cell death.

The implication is that if one could either make chemicals that stimulate this phosphatase or devise safe and effective gene therapies for elevating GADD34 activity, then perhaps the brain could be protected.

The big unknown question is what happens if the primary insult -- namely, accumulation of unfolded proteins -- is not addressed. Will the restoration of protein synthesis by itself provide a long-term solution?

It could even be argued that stimulating too much protein synthesis could be detrimental, by increasing the protein load on cells. Some portion of newly synthesized proteins routinely fails to fold properly, creating a need for ongoing homeostatic mechanisms that clear these unfolded proteins from cells.

These findings confirm the importance of protein misfolding as an initiator of neurodegeneration. They encourage future research aimed at devising strategies for modulating the cellular unfolded protein response as a possible means to improved treatments for the neurodegenerative diseases that plague us today and that will confront us even more in the decades ahead.

For Medscape, I'm John Reed.

 
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References

  1. Moreno JA, Radford H, Peretti D, et al. Sustained translational repression by eIF2á-P mediates prion neurodegeneration. Nature. 2012;485:507-511. Abstract

Authors and Disclosures

Author

John C. Reed, MD, PhD

Chief Executive Officer, Professor, Donald Bren Chief Executive Chair, Sanford-Burnham Medical Research Institute, La Jolla, California

Disclosure: John C. Reed, MD, PhD, has disclosed the following relevant financial relationships
Serve(d) as a director for: Isis Pharmaceuticals, Inc.; Clovis Oncology
Received a research grant from: AstraZeneca Pharmaceuticals LP; Johnson & Johnson Pharmaceutical Research & Development, LLC

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