International research team uncovers possible therapy for Parkinson's disease
Parkinson's disease is a devastating neurodegenerative disorder that affects nearly 1 million people in the United States, and more than 10 million worldwide.
Parkinson's disease is a devastating neurodegenerative disorder that affects nearly 1 million people in the United States, and more than 10 million worldwide.
Although Parkinson's is the most common form of progressive neurodegeneration, its pathogenesis is not well characterized, and treatments are limited. Major symptoms are movement disorders, difficulties in writing and speaking, and, in some cases, dementia.
A group of scientists from U.S. and Chinese institutions have found similarities between a mechanism in Parkinson's and in another more rare neurodegenerative disease, Pantothenate Kinase-Associated Neurodegeneration, PKAN. They report that their discovery, identifying a mechanism for repairing mitochondria, suggests a potential therapy for Parkinson's.
Their work appears in Nature Communications, May 3.
What causes Parkinson's?
It's estimated that about 10% of Parkinson's is caused by genetics, and 90% is due to environmental risks. The researchers note that mechanisms behind these causes are both intricate and mysterious. However, it's known that mitochondrial dysfunction is involved.
The authors describe key genes associated with Parkinson's, identified from research with people who have it. Certain mutations in these genes--PINK1, Parkin, and PRKN, are associated with early onset Parkinson's. The proteins encoded by those genes, the researchers write, are essential "in maintaining mitochondrial function, monitoring mitochondrial damage and initiating mitophagy...."
Mutations in these genes are linked to lower levels of important metabolites, such as Coenzyme A (CoA) and acetyl-Coenzyme A in Parkinson's and in PKAN, which was formerly known as Hallervorden-Spatz syndrome. PKAN is caused by pathogenic variants in the pantothenate kinase 2 (PANK2) gene. In humans, the authors note, there are four PANKs but only PANK2 is mitochondrial.
The discoveries
The researchers looked at the homologue of human PANK2 in Drosophila, which has the curious name of fumble or Fbl. They discovered that when Fbl is made deficient in fruit flies, it results in neurological damage and symptoms similar to those in Parkinson's patients.
For example, they note, the Fbl mutant is associated with "multiple defects, including a significant drop of eclosion rate, abnormal wing morphology (wing inflation), progressive locomotor dysfunction, lifespan shortening, infertility and broad neurodegeneration." (Eclosion is when an adult insect emerges from the pupal case.)
The authors also found that when elements of CoA were boosted, it benefited fruit flies that had loss of function due to Fbl deficiency.
The authors report, "In this study we uncovered a sophisticated and conserved interaction among PINK1, Parkin, and Fbl/PANK2, and their roles in the control of CoA/acetyl-CoA synthesis and mitophagy regulation. Fbl/PANK2 is subject to the mitochondria-localized translational regulation by PINK1 and Parkin, and Fbl/PANK2 overexpression can significantly suppress defects of PINK1 [loss of function]. This rescue is implemented by CoA and acetyl-CoA elevation...."
Through their experiments with Drosophila, the researchers were able to characterize the sophisticated mechanism that allows Fbl/PANK2 to regulate the elimination of damaged mitochondria, by interacting with PINK1.
They also note that pharmacological treatments present evidence of a connection between CoA synthesis and the genesis of Parkinson's. The combination of genetic and pharmacological rescue data, they write, both show an "ability of enhancing the CoA synthesis pathway."
Treatment strategies
Based on their experimental data, the researchers suggest, "Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype."
Further, they write, "Our results help better understand the communality of the two diseases, PD and PKAN, and may facilitate the development of new treatment strategies in the future."
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Y. Huang et al. Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism. Nature Communications, May 3, 2022.
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