Researchers Confer, Agree in Principle on Transmission Model in Neurodegenerative Disease

Virginia M-Y Lee, PhD, MBA, director of Penn’s Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania,  recently presented at the annual Ipsen Foundation meeting in Paris, where researchers convened to discuss an emerging concept in neurodegeneration: how brain diseases spread through the brain.

Recent media coverage has highlighted studies showing how diseases like Alzheimer’s, Parkinson’s and others spread through the brain. In her New York Times story on this discovery in Alzheimer’s disease, Gina Kolata notes that “Alzheimer’s disease seems to spread like an infection from brain cell to brain cell, two new studies in mice have found. But instead of viruses or bacteria, what is being spread is a distorted protein known as tau. ”

With the opportunity to get a first-hand account from one of the leading researchers investigating this new transmission model, I asked Dr. Lee a few questions about the 2012 Ipsen Meeting.

Science of Aging: What were the main takeaways from the conference?

Virginia M-Y Lee: Ipsen meetings have been going on for quite a while (since 1987). The goal of the meetings is to highlight emerging, new ideas in areas of research. Ipsen hosts the meeting in Paris, and the topics are selected on their broad-based impact.

This is an area that I wasn’t surprised that they selected for the neurodegenerative conference this year . Everybody they invited showed up.

The whole symposium was designed to demonstrate conceptually that the mechanism of spreading could be extended to almost all neurodegenerative diseases. Speakers presented on amyloid beta, tau, Alpha-synuclein (a-syn), Huntington’s disease and SOD1 and the overarching mechanism is on prion-like transmission of misfolded disease proteins. Stan Prusiner from the University of California San Francisco led off the meeting talking about the idea in prion disease, where a misfolded protein initiates cascades and perpetuates itself. The conference closed with Eric Kandel from Columbia University talking about a protein he discovered – a normal protein involved in development that has a prion domain, that he discovered in worms and has demonstrated in cells, but has not yet been shown in humans.

Science of Aging: Are there ways you can disrupt the spreading?

Dr. Lee: Basically, we don’t know how to stop the spreading or disrupt the interaction between the bad misfolded protein with the normal protein. We are still at an early stage where the neurodegenerative disease community is establishing both cell and animal models of disease protein transmission for amyloid beta, tau, and a-syn.

But, the concept of transmissions is potentially a common pathway for disease spreading and disease progression. If misfolding proteins spread to one part of brain, the neurons become dysfunctional.

If this is the lynchpin, we can try to come up with therapies. One we are exploring is immunotherapy. The best case scenario is to stop the spreading.

In order for the pathology to spread from neuron to neuron in animals:
Step 1. Misfolded disease protein must be released from the neurons.
Step 2. The misfolded protein needs to be taken up by an adjacent neuron.
Step 3. Once inside, the misfolded protein must expand by corrupting and recruiting endogenous normal protein.

If we can neutralize what is being released (step 1 ), we won’t have to figure out how to get a treatment inside the neuron. For instance, if we give an animal an antibody, a small amount may be able to neutralize what’s being released. (not try to get inside neuron, just stop what’s released).

Science of Aging: How does this change the scope of neurodegenerative disease research?

Dr. Lee: In my opinion, the transmission model is probably more correct than the current transgenic mouse models where a-syn protein are overexpressed.

In the next 3-5 years, there’s likely to be research showing that the transgenic mouse model may not be appropriate, and that the transmission model will more likely prevail.

Science of Aging: Is there a possibility that both the transmission and transgenic mouse models could be looked at together?

Dr. Lee: Yes, we have demonstrated transmission in transgenic mouse models by inoculating a-syn synthetic fibrils into a-syn transgenic mice.  The holy grail in the field is to demonstrate transmission in non-transgenic wild type animals but no one can do this successfully yet.

Science of Aging: What does this mean for patients?

Dr. Lee: New mechanisms mean there are new targets that we can use to identify drugs. Immunotherapy is one way, but other ways like expansion inside cells or interrupting the process in other ways are also possible.

Last year, we published a paper in Neuron showing that there are ways to create a-syn pathology in neurons grown in a dish. This neuron-based model can be optimized into an assay which can help us identify small molecules, antibodies, genes, and knockdown strategies to eliminate spreading. Thus, treatment strategies include small molecules or biologics.

Science of Aging: How do meetings like this help the field move forward?

Dr. Lee: This meeting really provided an opportunity for some of the leaders to get together and come to some consensus that this is a common mechanism that could reflect progression.

It’s great to get everyone together and see if they agree, share ideas. In this case, the observation in one system may help us halt the spreading in other diseases. This meeting, along with two meetings held recently in the United States, are the first meetings that got everyone together to address this. People are in agreement. Now we’ll move towards the next step – develop useful systems to study in cells and animals, and continue researching this mechanism across diseases.

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World Health Day 2012: Rethinking Aging Globally

Tomorrow, Saturday, April 7, is the World Health Organization (WHO)’s annual World Health Day. This year, the focus will bring attention to the rapidly aging population globally, and encouraging people to reduce stigmas and seek treatment for non-communicable diseases, to help people reach old age in the best possible health.

At Penn’s Institute on Aging, researchers and clinicians from across the University of Pennsylvania are working towards a common goal: to improve the health of older adults.

Penn Institute on Aging director John Trojanowski, MD, PhD, explains how we can help empower ourselves and each other to age successfully.

What will you do to help reduce the stigmas associated with aging in your community?

Walking a Quarter of a Mile to Stave off Disability

People unable to walk a quarter of a mile, the equivalent to one time around a track or 3-4 city blocks, are twice as likely to be hospitalized, warned Jack Guralnik, MD, PhD, MPH, at the latest Penn Institute on Aging Visiting Scholars lecture.

In this video, Dr. Guralnik, a professor of Epidemiology and Public Health at the University of Maryland School of Medicine, explains what researchers are finding, in terms of mobility prevalence and the dangers of disability. He also discusses a program that has been developed and is being studied which may be able to reverse mobility decline to prevent disability.

If you missed the live twitter coverage during the conference, we’ve included a transcript below, chocked full of interesting statistics and observations from Dr. Guralnik’s lecture.

[View the story “Jack Guralnik Visits Penn Institute on Aging” on Storify]