Study Rationale:
Mutations in the gene encoding the enzyme GBA1 are among the most common genetic risk factors for Parkinson’s disease (PD). These mutations compromise the stability and activity of GBA1, but the enzyme is also impaired in other genetic forms of Parkinson’s disease and in the sporadic form of the disorder. Therefore, strategies that improve these properties can provide valuable therapeutic approaches. We have generated nanobodies — small, fully functional antibody fragments — that bind to GBA1 to determine their ability to stabilize and activate the enzyme. Nanobodies displaying interesting properties in our laboratory tests have been selected for further study.
Hypothesis:
We propose to further characterize the interaction between GBA1 and selected nanobodies, and we will assess these nanobodies’ ability to improve GBA1 function and neuronal survival in cellular models.
Study Design:
Using standard molecular biological techniques, we will introduce the most promising nanobodies into PD cellular and neuronal models that carry the GBA1 mutation. We will direct the nanobodies to specific subcellular compartments and determine whether they can rescue the activity of the enzyme and protect the function of their target compartment. We will also explore how the nanobodies work by determining the 3D structure of the complex that each forms with GBA1; this information will allow us to design peptides that mimic the binding of the nanobodies to GBA1, producing an additional tool for preserving GBA1 function.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This study will deliver two different molecules able to restore PD cell function: nanobodies and nanobody-derived peptide mimetics. Both can be considered valuable approaches for the treatment of PD, including cases that are not associated with GBA1 mutation, because the enzyme is often impaired in other forms of the disease.
Next Steps for Development:
Next steps will include testing the most promising nanobodies and peptides in preclinical models of PD, beginning with those the feature GBA1 mutations. Ultimately we would also study additional models of genetic and sporadic PD. In parallel, the rescue of GBA1 impairment and neuronal defects could be investigated also in iPSC-derived neurons, which would represent a valuable human-derived model to evaluate Nbs and peptide effects in PD models.