In an exciting new study, researchers at Brigham and Women’s Hospital in Boston, MA, led by APDA Cotzias Fellowship* awardee Dr. Vikram Khurana, demonstrated a new role for the protein involved in Parkinson’s disease (PD) pathology, alpha-synuclein. In addition to alpha-synuclein interacting with vesicles, or small transport structures within the cell, this new study shows that alpha-synuclein also binds to structures known as P-bodies which are part of the cell machinery that regulates messenger RNA (mRNA), the intermediary molecule between DNA and the protein that it encodes. Normal binding of alpha-synuclein to the P-body helps to stabilize the mRNA. When too much alpha-synuclein is in the cell, this stability is compromised. This finding is extremely important as it not only gives us new insight into what is going wrong in the neurons of people with PD but identifies new targets for potential treatments. This work was published on June 9, 2022 in the medical journal Cell. APDA is proud to fund Dr. Khurana in is his mission to uncover the mysteries of PD.
Dr. Khurana answered questions about this exciting research:
Q. Can you briefly describe what your lab discovered?
A. The characteristic pathology of PD and related disorders (like dementia with Lewy bodies and multiple system atrophy) is the aggregation of a protein in brain neurons and glial cells called alpha-synuclein. The paper describes a new function for alpha synuclein and shows that this new function has relevance for human disease. Alpha-synuclein, a protein traditionally known to be involved with transport structures in the cell known as “vesicles”, is now found to have a double life. The very same part of the protein that interacts with vesicles also binds to structures known as P-bodies, machinery in the cell that regulate the expression of our genes through mRNAs. In neurons derived from PD patient stem cells and in human brain when alpha-synuclein abnormally accumulates, the physiologic structure and function of the P-body is lost, and patients who accumulate mutations in P-body genes appear to be at higher risk for PD.
Q. How will this help the PD field?
A. The paper gives new insight into the function of the protein known to be at the center of PD pathogenesis, alpha-synuclein. This is a protein that is being targeted by current therapeutics, but its actual function has been elusive. If a protein is targeted by therapy, it is important to know its function in order to determine the potential consequences of reducing its level or activity. This paper provides important information to fill our knowledge gap here. Second, the discoveries in this paper open up new potential targets for therapies that prevent or slow down the progression of PD and related synucleinopathies. Finally, the paper provides early evidence that mutations in P-body genes may contribute to human genetic risk of PD. PD may arise in different ways in different patients, and a “one size fits all” strategy may not work for the disease. The findings in this paper might help us “stratify” or “bin” patients into different categories and, in time, develop more targeted therapies for patients.
Q. What’s the next big question based on this work?
A. There are several. First, we need to better understand how the P-body machinery interacts with alpha-synuclein. For this, we need to develop a more structural understanding – purify the different components in a test tube and observe how they physically interact. Second, more clarity is needed on which of the P-body machinery components might be the best targets for a therapeutic intervention. Third, more detailed genetic studies are required to understand how much do mutations in P-body genes contribute to risk of PD and disease progression.
You can see Dr. Khurana discuss his work, supported by APDA, in this research roundtable discussion.
*The George C. Cotzias Memorial Fellowship is a three-year fellowship awarded by APDA to young neurologists who are establishing their careers in both research and patient care of PD. To be part of APDA’s mission of providing crucial early-phase research funding, consider a donation to APDA today.