Loss-of-function mutations in components of the PINK1/PRKN pathway lead to early onset Parkinson’s disease. Previous work by our company has shown that our compounds can amplify the activity of active-form PINK1, and thereby reduce common pathologies (like mitochondrial dysfunction and alpha-synuclein aggregation) seen in Parkinson’s disease. Our more recently genereated PINK1 activators are much more potent than our original compounds. Working with the Muqit lab at the University of Dundee, we will mechanistically characterize our compounds to better understand how they enhance the catalytic function of PINK1, and then look to translate our cell-based assay results into models of Parkinson’s disease.
We believe that Mitokinin’s compounds are acting directly on PINK1 to help increase the levels of active-form PINK1 in the presence of mitochondrial stress. We further believe that amplification of PINK1 will reduce the presence of pathologic alpha-synuclein species, leading to lower levels of neuron death.
Working with a well-validated cell line in collaboration with the Muqit lab, we will test the consistency and PINK1-specificity of MTK-458 in the Muqit lab’s assays. We will complement those cell-based studies with in vitro activity assays involving hPINK1 purified in an active form, as well as mitochondrially stabilized PINK1. Following mechanistic characterization of MTK-458, we will test whether MTK-458 treatment can rescue alpha-synuclein pathology in models injected with alpha-synuclein pre-formed fibrils.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
PINK1 amplification represents a first-in-class strategy for the treatment of Parkinson’s disease. If successful, Mitokinin’s compounds could transform the treatment of the disease, dramatically slowing or halting progression.
Next Steps for Development:
The in vivo models proposed in this study will provide important proof-of-concept data for further development of MTK-458 in Parkinson’s disease.