Northwestern Medicine scientists have uncovered a new mechanism by which mutations in the gene parkin contribute to familial forms of Parkinson’s disease. The team used transcriptomics, metabolomics, and super-resolution microscopy, to identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin-related PD. The discovery, the researchers say, opens a new avenue for development of Parkinson’s therapeutics.
Their work was published in Science Advances. The first author of the study is Wesley Peng, who recently completed the MD-PhD program at Northwestern and currently serves as a neurology resident at Mass General Brigham and Harvard Medical School.
Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson’s. Among the variety of cellular processes it helps regulate, loss of parkin’s E3 ligase activity is thought to play a pathogenic role in both inherited and sporadic PD.
A prior study found that lysosomes and mitochondria form contacts with each other. This work was published in Nature by colleagues and Dimitri Krainc, senior author of the current study and chair of neurology at Northwestern University Feinberg School of Medicine. After this initial discovery, Northwestern scientists went further to understand the function of these contacts in Parkinson’s disease.
Parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions has not been fully determined.
Mitochondria are the main producers of energy in cells, and lysosomes recycle cellular debris that accumulates during normal function of human cells. These organelles are especially important in the brain because neurons are highly dependent on energy production by mitochondria, and because of their activity, neurons produce an abundance of cellular debris that must be cleared by lysosomes.
In the new study, the Northwestern investigators report that lysosomes help mitochondria by providing key metabolites for their function. Mitochondria must import many of their essential ingredients, but it has not been well-known where some of these metabolites come from. Lysosomes also serve as recycling factories in cells and, therefore, produce many breakdown products that could be used by other organelles such as mitochondria.
The Northwestern scientists found that lysosomes provide important amino acids that support the function of mitochondria. However, they also found that in some forms of Parkinson’s disease, lysosomes cannot serve as a “helping hand” to mitochondria because the contacts between the two organelles are disrupted. This results in dysfunctional mitochondria and ultimately degeneration of vulnerable neurons in Parkinson’s disease.
They write, “Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.”