The goal of the proposed work is to pursue efforts in drug development for Parkinson's disease that are aimed at the underlying cause. The recent discoveries of individual genes that are linked to the inheritance of PD have provided critical insights into two types of proteins: those that promote PD and those that help prevent the illness in humans.
Among the growing list of single genes linked to PD to date, increased production of the alpha-synuclein protein and the loss of Parkin expression are considered important events in the development of parkinsonism. We seek to pursue the following two goals for future PD therapy: reduce the amount of alpha-synuclein; and, increase the levels of Parkin. Our cell-based screening of a library of small molecules will take place at the Laboratory of Drug Discovery in Neurodegeneration at Brigham and Women's Hospital (LDDN; director: Dr. Ross Stein). The LDDN is run by a team of scientists with industry experience that oversees a robotic facility and houses a small molecule library; we will embed a scientist at the LDDN and closely collaborate with its staff to first carry out screening rounds that seek to promote the increased expression of Parkin and the reduction of total alpha-synuclein in cultured cells.
In a second step, we seek to validate a group of selected 'hits' from the alpha-synuclein- and Parkin-directed screening efforts and evaluate the specificity of these compounds.
Final Outcome
Dr. Schlossmacher attempted to screen the FDA approved library of small molecules to determine whether any compounds reduce endogenous alpha-synuclein in neural cells. The group identified compounds in the rapamycin and autophagy class of molecules that reduce levels of alpha-synuclein protein as measured by sandwich ELISA. The group is now following up on these hits by carrying out cellular studies that address the effective range of individual drugs, the rates of SNCA transcription versus alpha-synuclein degradation by lysosomal enzymes, and validation in primary neurons.