New treatment strategy may boost nerve cell function in Parkinson’s

Novel mechanism seen as key in early-onset Parkinson's disease

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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An illustration shows a close-up view of mitochondria, known as the powerhouse of a cell.

Researchers have found a novel mechanism through which mutations in a gene called PRKN, linked with early-onset Parkinson’s disease, play a crucial role in familial forms of the disorder.

The study found that PRKN gene mutations lead to a disruption in the communication between two vital components within the cell, lysosomes and mitochondria. This disruption prevents mitochondria — the cell’s powerhouses and key for the maintenance of nerve cells — from feeding on lysosomes’ amino acids, causing them to become dysfunctional.

This discovery paves the way for new possibilities in the development of Parkinson’s therapeutics, according to the researchers.

“Findings from this study suggest that dysregulation of mitochondria-lysosome contacts contributes to … Parkinson’s disease,” Dimitri Krainc, MD, the study’s lead author, said in a press release, adding, “We propose that restoring such mitochondria-lysosome contacts represents an important new therapeutic opportunity for Parkinson’s disease.”

The study, “Parkin regulates amino acid homeostasis at mitochondria-lysosome contact sites in Parkinson’s disease,” was published in the journal Science Advances.

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An image of mitochondria, a component of cells that supply the cell's with energy and are essential to cellular health.

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Investigating mutations linked to early-onset Parkinson’s disease

Parkinson’s hallmark is the progressive loss of dopaminergic neurons — nerve cells that produce the neurotransmitter dopamine, a chemical messenger essential for muscle control.

Early-onset Parkinson’s is commonly linked with the presence of mutations in certain genes associated with the disease. Specifically, mutations in the PRKN gene, which carries the instructions for a protein called parkin, are the most common genetic cause of early-onset disease.

Parkin is an enzyme that chemically tags damaged mitochondria for degradation in another cell compartment, the lysosome. This process ensures that defective mitochondria are removed, preventing the accumulation of damaged organelles and maintaining cellular health.

However, whether parkin plays additional roles related with the cross-talk between mitochondria and lysosomes — and whether this is important in Parkinson’s —remained unknown.

A team of researchers led by Krainc, who serves as chair of neurology and director of the Simpson Querrey Center for Neurogenetics at the Northwestern University Feinberg School of Medicine, in Illinois, had previously found that lysosomes and mitochondria established contacts with each other.

To follow up on these results, the team used dopaminergic neurons created from induced pluripotent stem cells (iPSCs) of a patient with mutated PRKN. The researchers discovered that the contact sites between mitochondria and lysosomes were reduced when compared with the nerve cells corrected for this mutation (controls). iPSCs are able to generate almost any type of cell in the body.

Several deep analyses of the cells were then performed. These included transcriptomics, or the study of all messenger RNAs, which carry the genetic information encoded in genes, and metabolomics, which is a global analysis of all metabolites, or small signaling molecules that arise during chemical reactions that occur within a cell.

The results revealed that the metabolism of amino acids — the building blocks of proteins — was reduced in Parkinson’s nerve cells. Both mitochondria and lysosomes are critical for amino acid storage and metabolism.

The researchers then postulated that the loss of contacts between mitochondria and lysosomes due to a deficiency of parkin contributed to the amino acid defects. Indeed, restoring the contacts between both compartments partially rescued the amino acid levels in the mitochondria and lysosomes.

Mitochondria and lysosomes were then isolated from Parkinson’s dopaminergic neurons and their amino acid content was analyzed separately.

The experiments revealed a dynamic between both compartments: while mitochondria showed a deficiency in several amino acids, these were accumulating in lysosomes.

The results suggest that lysosomes work as a reserve of amino acids for the mitochondria via the establishment of contacts. If disrupted, the flow of amino acids is affected and the mitochondria become dysfunctional, ultimately leading to the degeneration observed in nerve cells in Parkinson’s disease.

Modulating the contacts between both compartments “may serve as a potential therapeutic strategy for restoring metabolic defects in disease,” the researchers wrote.