Ralph Nixon, M.D., Ph.D. | Alzheimer's Association

Ralph Nixon, M.D., Ph.D.

Nathan S. Kline Institute for Psychiatric Research
Orangeburg, New Jersey
2003 Zenith Fellow

Unraveling the Mechanisms of Protein Accumulation in Alzheimer's Disease

One common mechanism involved in Alzheimer's and other neurodegenerative diseases is the abnormal build-up of naturally occurring proteins to form clumps in the brain. Dr. Ralph Nixon, a Temple Foundation and Zenith Fellows awardee, has been a pioneer in the area of understanding how proteins are made, shuttled through cells and degraded. Abnormal forms of a protein are usually degraded through a process called "autophagy" in which they are transported and broken down enzymatically in specialized cellular compartments called endosomes and lysosomes.

Autophagy is essential to the normal function of cells. Defects in this system are now known to play a role in cancer and many neurodegenerative diseases. The fundamental importance of this process was recognized when Dr. Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Physiology or Medicine for his discoveries in the 1990s that revealed the key genes and molecular mechanisms involved in autophagy and the importance of this process to cellular function.

Dr. Nixon has pioneered the discovery of new biological pathways that may explain how autophagy and the endosomal/lysosomal pathway go awry and cause proteins to accumulate in and around nerve cells. It is this accumulation that is thought to cause nerve cells to die in Alzheimer's and other neurodegenerative diseases. Since his 2003 Zenith Award, Dr. Nixon has been awarded nearly $15 million in National Institutes of Health (NIH) funding related to Alzheimer's and other dementias research. Dr. Nixon and colleagues have made several key discoveries related to the role of autophagy in Alzheimer's. Dr. Nixon has found that proteins associated with Alzheimer's disease, including presenilin-1 (PS-1) and amyloid precursor protein (APP), may affect the function of endosomal/lysosomal pathway and potentially contribute to the accumulation of toxic beta-amyloid in the brain. In addition, his research team has been instrumental in uncovering the specific proteins that cause endosome dysfunction and trigger a cascade of events that lead to nerve cells loss. Because endosome dysfunction occurs very early in the disease process, therapies that target this process may help slow or halt the disease process before irreversible damage occurs.

Dr. Nixon's leading role in defining these biological pathways has paved the way for the exploration of new therapeutic strategies that could target abnormal protein clumping and accumulation in Alzheimer's and many other brain diseases. Early-phase clinical trials have begun testing the safety of molecules that stimulate autophagy, which may have broad potential in treating many types of dementia.




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