New Approaches to Tackling Neurodegenerative Disease
Ana Maria Cuervo, MD, PhD, from the Albert Einstein College of Medicine, discusses her research and the role of autophagy in neurodegenerative diseases.
Published May 25, 2017
By Academy Contributor
Autophagy is a critical process by which cells “recycle” their damaged or unnecessary components. A complex and tissue-dependent cellular pathway, malfunctioning autophagy plays a role in a wide range of diseases, including neurological disorders, cancer, infectious disease, and obesity. Recently, Ana Maria Cuervo, MD, PhD, the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases at the Albert Einstein College of Medicine, discussed her research and the role of autophagy in neurodegenerative diseases.
A geriatrician by training, Dr. Cuervo was one of the first scientists to closely study autophagy. Her initial interest in the topic was piqued by very early studies that suggested the effectiveness of the lysosome—the site in the cell where autophagy takes place—decreases with age. She observed that lysosomes in older animal tissues were very abnormal, enlarged, and filled with un-degraded material.
Autophagy’s role as a cellular recycling system connects it to neurodegenerative disease. When autophagy is malfunctioning, material accumulates in cells, damaging neural pathways. “If a neuron accumulates all these vesicles full of garbage, they might not be initially toxic, but as they accumulate they start to interfere with the normal traffic and activities and will contribute to toxicity and cell death. This process is incomplete autophagy, or autophagy gone wrong, and is outside the normal process.”
Macroautophagy, Microautophagy, and Chaperone-mediated Autophagy
Autophagy is divided into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), which play distinct though related roles, each with its own mechanisms. The discovery of CMA by Dr. Cuervo and colleagues changed the wider understanding of autophagy. Previous opinion held that autophagy was not selective, and the prevailing view was, “basically, if a cell is hungry the lysosome will just grab whatever happens to be nearby, regardless of condition, to get more energy. However, we — and by we, I mean me, my PhD mentor, Erwin Knecht and postdoc mentor, the late J. Fred “Paulo” Dice — had the idea that lysosomes are selective. They only trap and degrade the damaged proteins, not the healthy ones.”
This hypothesis was not initially well received, but follow-up experiments in the late 1990s and early 2000s proved Dr. Cuervo was right. In one experiment that highlighted the importance of CMA, Dr. Cuervo studied mice with the gene for a critical component of CMA called LAMP-2A deleted. These mice “very early on develop a metabolic syndrome that is something that you see characteristically in aging,” including disorders such as diabetes, hypertension, and obesity. Mice with the LAMP-2A gene deleted specifically in neurons “are very interesting because they develop both motor problems that resemble Parkinson’s, but also memory and cognitive problems that resemble Alzheimer’s.”
Autophagy’s Role in Neurological Function
Interestingly, Dr. Cuervo found that mice with extra LAMP-2A protein are resilient to stress as they age. “Similar to other forms of autophagy, CMA, the LAMP-2A pathway is very important in maintaining neuronal activity and function. Autophagy declines as people age, and that is a risk factor for common neurodegenerative diseases.” Dr. Cuervo pointed to the importance in aging research of not just extending lifespan, but extending healthspan — not only to live longer, but to live healthier. Her findings suggest that therapies that prevent the decline of LAMP-2A with aging may prove useful in thwarting or treating neurodegenerative disease, and increasing healthspan overall.
Despite these exciting results, many unanswered questions remain about autophagy’s role in neurological function. Furthermore, translating what is known into therapies is challenging, due to the complexity of the pathways, the difficulty in developing drugs that target each pathway specifically, and the current lack of a clinical readout that identifies when and how autophagy has gone awry.
Communicating, Discussing, Testing
“It would be very interesting to know if the neurons that die first, causing a neurodegenerative disorder, die because they are less able to activate a particular form of autophagy, or because they have lower activity. If we knew which autophagy pathway to target we could develop potential therapeutic approaches.” Dr. Cuervo noted that a major limitation is, “trying to extrapolate [measurements of autophagy in the blood and in skin fibroblasts] to what happens in the brain. Clinically, there is no good way to measure autophagy in normal, healthy people. Nothing can tell you, ‘Oh this person has good autophagy or bad autophagy in the brain. We should do this treatment.’”
Another complication is autophagy’s role in other diseases. For example, in general for neurodegenerative disease potential therapies would promote autophagy, to clear out debris causing cell death and malfunction. In contrast, because it is pro-survival, inhibiting autophagy may prove a useful cancer therapy, by reducing the capacity of cancer cells to survive.
Dr. Cuervo finished the interview by noting that for scientists to make advances, “it’s essential to communicate and share your ideas with other investigators because you can be wrong — and I have been wrong so many times before! You need colleagues to discuss and challenge your ideas. Science isn’t about being isolated in a lab. Science is about communicating, discussing, and then testing.”
