Gaucher and Parkinson’s: Identifying one target for two diseases

2015

Challenge

Both Parkinson’s disease and the rare lysosomal disorder Gaucher disease need new therapeutic approaches and effective treatments that better address the root causes of the disorders.

Advance

IRP researcher Ellen Sidransky, M.D., and colleagues at NCATS Chemical Genomics Center collaborated with Kansas University researchers to identify chemical chaperones—molecules that can help to stabilize or correct enzyme defects—for glucocerebrosidase (GCase), an enzyme missing in Gaucher disease that is essential for cells to break down cellular waste. The team then tested these chaperones in models of other diseases of cellular waste, including Parkinson’s disease. The chaperones rescue the cell’s ability to deal with noxious waste and prevent cellular degeneration.

Impact

The work now has been licensed to industry for further development with the aim of yielding new therapies for Parkinson’s disease and other neurological disorders. Researchers at NIH continue to explore this novel biology and its possible relevance to other diseases as well.

Publications

Aflaki E,  Stubblefield BK, Maniwang E, Lopez G, Moaven N, Goldin E, Marugan J, Patnaik S, Dutra A, Southall N, Zheng W, Tayebi N, Sidransky E. (2014). Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs. Sci Transl Med. 6(240), 240ra73.

Patnaik S, Zheng W, Choi JH, Motabar O, Southall N, Westbroek W, Lea WA, Velayati A, Goldin E, Sidransky E, Leister W, Marugan JJ. (2012). Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. J Med Chem. 55(12), 5734-48.

Zheng W, Padia J, Urban D, Jadhav A, Goker-Alpan O, Simeonov A, Goldin E, Auld D, LaMarca M, Inglese J, Austin C, Sidransky E. (2007). Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease. Proc Natl Acad Sci U S A. 104(32), 13192-7.