Dr Virginia Lee, Centre for Neurodegenerative Disease Research, University of Pennsylvania
The CNDR, within the Perelman School of Medicine at the University of Pennsylvania (UPenn), looks at some of the world’s most prevalent ageing-related neurodegenerative diseases such as Alzheimer’s disease (AD) and related disorders. In this discussion, Dr Virginia Lee outlines the Centre’s efforts to implement its mission, which is to discover effective drugs and efficient treatments for AD, Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)
Could you begin by discussing the origins of the Centre for Neurodegenerative Disease Research (CNDR)?
John Trojanowski, my partner and I came to UPenn in 1980. At first, we were both involved with distinctly different research projects, but, over time, we found ourselves working together and sharing an interest in AD and related neurodegenerative diseases. Collaborating allowed us to combine our skill sets harmoniously, as John’s background is in neuropathology and neuroanatomy, and I am trained as a neuroscientist and a biochemist. Since many of the neurodegenerative diseases require multidisciplinary approaches to make real progress towards finding better ways to understand, diagnose and treat these disorders, it seemed like a great step forward. By the time we established the Centre in the early 90s, we were already collaborating with clinicians as they were the ones that would see and recruit patients. Our main goal is to systematically identify and isolate all proteins found in major neurodegenerative diseases such as AD, PD, FTLD and ALS.
What is the range of diseases on which you conduct research?
We work with four major diseases, including AD, PD, a less well-known form of dementia collectively referred to as FTLD, and ALS. We decided on these diseases because the core problem they all share is protein aggregates or clumps due to the misfolding and aggregation of specific disease proteins in the brain, which we hypothesised to be extremely important for disease course and pathology, as well as pathogenesis, therefore highly relevant targets for biomarker and drug discovery efforts.
When we began, we knew very little about the identity of the proteins that comprise the plaques and neurofibrillary tangles of these diseases, and we wanted to systematically purify and identify these proteins. We started with tau in 1991, which was followed by synucleinopathies like PD in 1998, and then TDP in 2006, which served to link ALS and FTLD together mechanistically. We do not study all neurodegenerative diseases, but focus on those that share common mechanisms of protein misfolding and also are major public health challenges. There is a shared mechanism in which all of these diseases eventually aggregate (cluster) in pathology, and this is what we think is responsible for the diseases themselves. We focus on understanding their pathobiology and use this information to come up with novel disease-modifying therapies and informative biomarkers.
The Centre investigates the causes and mechanisms of neurodegenerative diseases that occur more frequently with advancing age. Why are these diseases age-related?
This is the 64 million dollar question! I think that there is a lot of speculation and no real answers to the age-related issue. One assumption is that our metabolism slows down or changes as we age, and this may have some impact on how these proteins are handled and degraded when they become effete, damaged, or non-functional. I think that we all accumulate mutations over time, but the majority of them are not harmful to us, but when they affect the genes encoding the disease proteins we study, they could be genetic causes of disease. It seems that some of the proteins we study may be misfolded, even when we are young, although our bodies have a way of degrading or eliminating them. As one ages, the mechanisms for eliminating them are impaired, and for these and other reasons we still need to discover, the proteins begin to accumulate as undergraded protein debris, or ‘brain trash’, that acts like a toxic landfill in the brain. However, this is a hypothesis that needs further testing and research to confirm or discard.
Could you explain the molecular mechanisms that might cause this degeneration?
With molecular mechanisms, we believe that despite these proteins’ diverse functions, what precipitates and consequentially leads to aggregation is an alteration in their function and metabolism, and this loss of function by the disease protein could have deleterious consequences in the brain. However, there is another way disease proteins can cause disease and that is known as a gain-of-function that is toxic. This may occur when normal proteins accumulate as pathology and become misfolded. We think that they play a role in eventually causing the demise of the neurons. This is a common mechanism that, in the last few years, has had tremendous attraction in terms of understanding the misfolding of the proteins into pathological conformers.
Notably, Heiko Braak, a neuropathologist in Germany took 1,000 AD brains and quantified the pathology in each one. Braak divided the brains into three categories – some had low pathology, others medium and the remaining had high pathology. I refer here to his work on neurofibrillary tangles formed by misfolded tau proteins, which are one of two major pathologies in AD brains.
Intriguingly, Braak found that all of the brains with low pathology were always identified as having this pathology start in the same location, while brains with medium amounts of tangles seemed to be consistent with the notion that there was spread of this tangle pathology across interconnected areas of the brain and similarly for the high-tangle pathology brains. Thus, Braak and colleagues hypothesised that tangle pathology can spread in AD, which may also correlate with the progression of the disease.
We know that AD and PD are not infectious, but that still doesn’t negate the fact that a misfolded protein with the ability to corrupt the normal protein in a cell could exist for these diseases. In the last five or six years there has been increased interest in testing this hypothesis to determine whether this is how these pathologies progress and spread in the brains of patients. Now, we are looking for a shared molecular mechanism of misfolded proteins that are able to corrupt normal proteins and eventually form more widely disseminated pathologies in the form of plaques, tangles or Lewy bodies, which, in turn, could be transferred or transmitted to neighbouring cells.
What advances in understanding Alzheimer’s disease has the Centre made? Are you able to conduct clinical trials on patients? How responsive are families of the patients to this research?
The Centre has a long history of working with tau proteins. One major contribution we have made towards AD was back in the 90s when we demonstrated that tangles were comprised of tau protein. Once you have the identity of the tangle-forming protein, then you can study the biology of this protein and the pathobiology of the tangles. Our studies on tau showed that it functions to stabilise microtubules in cells, which are protein transport structures). When tau proteins are sucked into forming tangles to eventually form tangle pathology, they are ‘missing in action’, that is no longer able to stabilise the microtubule.
We argued that we could offset this loss of tau with a small molecule drug that could replace the function of tau and stabilise microtubules, thereby restoring axonal transport to normal levels to slow down or reverse the progression of AD and prevent neurons from dying. In fact, pharmaceutical companies were interested in such compounds to stabilise microtubules to prevent cancer cells from replicating, and since neurons do not replicate and would not be affected in the same way cancer cells are by such drugs, this idea wasn’t so far-fetched. One of the most widely used drugs to treat cancer is taxol, a classic microtubule stabiliser, so we started with taxol first. However, while our initial effort with taxol showed promising beneficial effects in a transgenic mouse model of tau pathology, the effects of taxol were limited because of its limited ability to get into the brain. We then identified another series of compounds called epothilones and showed that one of these compounds, epothilone D, or EpoD, readily entered the brain. Then, in a series of subsequent studies in transgenic mouse models of AD-like tangle pathology, we showed that we could prevent tangle formation and the death of neurons, thereby demonstrating the potential efficacy of this strategy to treat AD. We have learned that a pharmaceutical company is taking EpoD into clinical trials for AD. In the meantime, we pursue other studies that will help us to prove our concept that stabilising microtubules may help patients with AD and to look for even better types of microtubule stabilisers for this purpose.
Alzheimer’s and Parkinson’s disease receive a lot of media attention. Does this affect the funding that research centres are able to attain? How do you attract funding for less well-known illnesses?
AD and PD are receiving the public attention they deserve, but too little funding to take advantage of all the opportunities to advance the pace of finding disease-modifying therapies. We do receive some donations from families whose loved ones have died from these diseases, and that has been a big help, especially with declining National Institutes of Health (NIH) funding now. But we can and want to do more, and it is limited resources – particularly for high-risk, high-reward pre-clinical studies not typically funded by the NIH – that prevents us from doing so.
How far-reaching is CNDR’s work? To what degree does it extend outside your laboratories? What other research organisations do you include among your partners?
Many areas of disease research are moving towards a translational phase, which facilitates collaboration, particularly in the domain of biomarkers. We collaborate with centres throughout the U.S. and through a programme called the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This receives both private funding from pharmaceutical companies and NIH funding to help identify early biomarkers for AD. The initiative has been very successful, and we have learned a lot about AD, how it starts and how it relates to the pathology. The CNDR is a major site for biochemical biomarkers and for ADNI. We use a similar type of method in collaboration with the Parkinson’s Progression Marker Initiative funded by the Michael J Fox Foundation.
At the moment, what is the target of your personal research?
One of the more unique aspects of the CNDR is that we have an academic biotech company-like approach to drug discovery within the Centre that is able to carry out drug discoveries for AD, PD, ALS and FTLD. My major focus is on the basic sciences and understanding the biology and functionality of the molecules studied in these multiple diseases, and how they become misfolded.
I am personally very excited about research ongoing now in our Centre to elucidate mechanisms of the transmission and spreading of disease proteins in AD, PD, ALS and FTLD. This represents one of the exciting areas of research for me. I want to study the molecular mechanisms of how misfolded disease proteins arise, and become these aggregates that eventually kill neurons. A basic understanding of the biology behind this would create fresh opportunities for therapeutic intervention.