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. 2019 Jul 24;9(8):296.
doi: 10.3390/biom9080296.

The Michael J. Fox Foundation for Parkinson's Research Strategy to Advance Therapeutic Development of PINK1 and Parkin

Shalini Padmanabhan  1 , Nicole K Polinski  2 , Liliana B Menalled  2 , Marco A S Baptista  2 , Brian K Fiske  2
Affiliations

The Michael J. Fox Foundation for Parkinson's Research Strategy to Advance Therapeutic Development of PINK1 and Parkin

Shalini Padmanabhan et al. Biomolecules. .

Abstract

The role of mitochondria in Parkinson's disease (PD) has been investigated since the 1980s and is gaining attention with recent advances in PD genetics research. Mutations in PRKN and PTEN-Induced Putative Kinase 1 (PINK1) are well-established causes of autosomal recessive early-onset PD. Genetic and biochemical studies have revealed that PINK1 and Parkin proteins function together in the same biological pathway to govern mitochondrial quality control. These proteins have also been implicated in the regulation of innate and adaptive immunity and other mitochondrial functions. Additionally, structural studies on Parkin have delineated an activation mechanism and have identified druggable regions that are currently being explored by academic and industry groups. To de-risk therapeutic development for these genetic targets, The Michael J. Fox Foundation for Parkinson's Research (MJFF) has deployed a strategic funding and enabling framework that brings together the research community to discuss important breakthroughs and challenges in research on PINK1-Parkin biology, supports collaborative initiatives to further our understanding within this field and develops high-quality research tools and assays that are widely available to all researchers. The Foundation's efforts are leading to significant advances in understanding of the underlying biology of these genes, proteins and pathways and in the development of Parkinson's therapies.

Keywords: PINK1; Parkin; Parkinson’s disease; antibodies; biomarkers; genetic; mitochondria; mitophagy; therapeutic development.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PTEN-Induced Putative Kinase 1 (PINK1) and Parkin pathway preclinical tools and animal models (a) The multiple players within the PINK1-Parkin-mitophagy pathway are indicated. Upon mitochondrial damage, PINK1 is stabilized on the mitochondrial membrane and gets activated. Once active, PINK1 phosphorylates ubiquitin that in turn binds to Parkin and causes Parkin translocation to the mitochondria. PINK1 also phosphorylates Parkin in the mitochondria that results in a conformational change in Parkin and renders it fully active. Parkin then ubiquitinates itself and several other mitochondrial proteins, the most prominent of which are listed in the figure. This labels the damaged mitochondria for degradation by the lysosome (mitophagy); (b) The various tools generated and distributed through the Michael J. Fox Foundation (MJFF) are listed. For detailed information on the status of their availability and distribution partner, please visit www.michaeljfox.org/toolscatalog.
Figure 2
Figure 2
Therapeutic approaches to increase PINK1-Parkin mediated mitophagy. The schematic indicates the proteins within the pathway that are currently being targeted for developing PD therapies, along with the therapeutic approach being pursued.
Figure 3
Figure 3
PINK1-Parkin pathway biomarkers. The schematic demonstrates the three essential phases for a biomarker assay: development, optimization and validation. Most biomarker efforts for PINK1 and Parkin fall under the assay development and assay optimization phases. MJFF-funded studies are listed along with the platform used for analysis in parenthesis. The assay development efforts use recombinant proteins while assay optimization efforts are in PBMCs derived from PINK1 and/or PRKN mutation cases and controls.
See this image and copyright information in PMC

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