Michael J. Fox Foundation Commits up to $2 Million to Address "Critical Challenges" in PD
“LRRK2 and alpha-synuclein are only two of multiple therapeutic targets that researchers have identified as holding potential to yield improved treatments for PD, possibly by slowing or stopping disease progression,” said Sarah Orsay, the Foundation’s chief executive officer. “Yet each is limited by distinct challenges that severely impede progress. Critical Challenges aims to move the entire field forward by encouraging scientists to tackle the difficult studies required to translate these genetic laboratory discoveries into new treatments.”
Gene Johnson, PhD, the Foundation’s chief scientific advisor, said: “The concept of the Critical Challenges program is a natural evolution of previous MJFF programs seeking a broad range of investigator-initiated projects in particular topic areas of interest. Critical Challenges, however, differs in that the Foundation is asking researchers to focus specifically on a key question hindering progress in a given field in order to help move research more effectively to the next stage.”
Leveraging the expertise of both its Research Programs staff and its Scientific Advisory Board, MJFF identified and prioritized several specific research challenges. The decision was made to focus first on genetic contributions to PD, as these may provide critical insight not only into underlying disease etiology and pathogenesis, but also potential therapeutic targets.
Recent discoveries show that mutations in the LRRK2 gene may account for as much as six percent of all familial PD cases and may underlie one to two percent of cases previously thought to be sporadic in nature, suggesting that it is a very important target for PD research. The protein product of the LRRK2 gene appears to have kinase activity. Kinases regulate the function of other proteins, and are typically involved in cell signaling pathways. Intriguingly, certain PD-associated mutations cause an increase in LRRK2 kinase activity, suggesting that this activity may play a central role in Parkinson’s pathogenesis. Additionally, kinase activity is often an attractive target for drug development.
Despite evidence supporting enhanced kinase activity as the underlying pathological mechanism of mutant LRRK2, it has yet to be conclusively demonstrated that this can result in dopamine neuron loss in the brain. (Results to date have looked only in cells grown in the laboratory dish.) Thus, the first challenge asks applicants to propose studies that can determine definitively whether altered LRRK2 kinase activity causes PD-related neurodegeneration in an intact animal brain. If confirmed, these findings would greatly accelerate drug discovery efforts to identify compounds that can modify LRRK2 kinase activity.
Alpha-synuclein is of great interest to Parkinson’s researchers because it is a major constituent of Lewy bodies, protein clumps that are the pathological hallmark of PD. Furthermore, genetic studies have shown that mutations in the alpha-synuclein gene or even having extra copies of the normal gene can lead to PD in rare cases. Yet despite intensive study over the last ten years, significant questions about alpha-synuclein’s role in the healthy and diseased brain remain unanswered. For the development of potential therapies, a critical debate revolves around whether blocking the protein’s aggregation, simply lowering its levels in the brain or modulating the protein in some other way would prevent PD progression.
Researchers seeking to take on the alpha-synuclein challenge should design experiments that definitively determine in an intact animal brain the specific abnormal characteristic of alpha-synuclein that ultimately triggers the cascade of events leading to neuronal dysfunction.
The Foundation has committed up to a total of $2 million — $1 million for each challenge — to fund projects with a budget maximum of $400,000 and duration of up to two years.