Gene Mutation Discovery Reveals New Therapeutic Target for Parkinson’s Disease

A Northwestern Medicine examine opens a brand new avenue of analysis in neurodegenerative problems, by highlighting the significance of direct communication and collaboration between mobile organelles within the pathogenesis of those problems.

Restoring contacts between mitochondria and lysosomes improves neuronal perform.

  • Contacts between lysosomes and mitochondria are damaged because of Parkinson’s mutation
  • Lysosomes can’t ‘feed’ mitochondria with essential metabolites

Northwestern Medicine scientists have uncovered a brand new mechanism by which mutations in a gene parkin contribute to familial types of Parkinson’s illness. The discovery opens a brand new avenue for Parkinson’s therapeutics, scientists report in a brand new examine.

Cellular Dysfunction in Parkinson’s

The Northwestern scientists found that mutations in parkin lead to a breakdown of contacts between two key staff within the cell – lysosomes and mitochondria.

Mitochondria are the principle producers of power in cells, and lysosomes recycle mobile particles that accumulates throughout regular perform of our cells. These organelles are particularly essential in our brains as a result of neurons are extremely depending on power manufacturing by mitochondria, and due to their exercise, neurons produce an abundance of mobile particles that have to be cleared by lysosomes.

In a previous examine, printed in Nature, Dr. Dimitri Krainc, chair of neurology and director of Simpson Querrey Center for Neurogenetics at Northwestern University Feinberg School of Medicine, and his group found that lysosomes and mitochondria kind contacts with one another. After the preliminary discovery, Northwestern scientists tried to grasp the perform of those contacts in Parkinson’s illness.

Inter-Organelle Communication in Parkinson’s

In the brand new examine printed on July 19 within the journal Science Advances, the investigators report that lysosomes assist mitochondria by offering key metabolites for their perform. Mitochondria should import a lot of their essential elements, nevertheless it has not been well-known the place a few of these metabolites come from. On the opposite hand, lysosomes function recycling factories in cells and, due to this fact, produce many breakdown merchandise that may very well be utilized by different organelles corresponding to mitochondria.

In this work, scientists discovered that lysosomes present essential amino acids that assist the perform of mitochondria. However, additionally they discovered that in some types of Parkinson’s illness, lysosomes can’t function a “helping hand” to mitochondria as a result of the contacts between the 2 organelles are disrupted. This ends in dysfunctional mitochondria and finally degeneration of weak neurons in Parkinson’s illness.

“Findings from this study suggest that dysregulation of mitochondria-lysosome contacts contributes to the Parkinson’s disease pathophysiology,” stated Krainc, the examine’s corresponding creator. “We propose that restoring such mitochondria-lysosome contacts represents an important new therapeutic opportunity for Parkinson’s disease.”

Implications and Future Directions

From a broader perspective, this examine opens a brand new avenue of analysis in neurodegenerative problems, by highlighting the significance of direct communication and collaboration between mobile organelles within the pathogenesis of those problems.

Published in Science Advances, the title of the examine is “Parkin regulates amino acid homeostasis at mitochondria-lysosome contact websites in Parkinson’s illness.”

Reference: “Parkin regulates amino acid homeostasis at mitochondria-lysosome contact sites in Parkinson’s disease” by Wesley Peng, Leonie F. Schröder, Pingping Song, Yvette C. Wong and Dimitri Krainc, 19 July 2023, Science Advances.
DOI: 10.1126/sciadv.adh3347

The first creator of the examine is Dr. Wesley Peng who not too long ago accomplished the medical scientist training program (MD-PhD) at Northwestern and at present serves as a neurology resident at Mass General Brigham and Harvard Medical School. Other contributors to the examine embody Leonie Schroder, Pingping Song and Yvette Wong.

The examine was supported by the next National Institute on Aging grant AG066333, National Institute of Neurological Disorders and Stroke (NINDS) grants NS109252 and NS122257, all from the National Institutes of Health.

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