‘Clueless’ Gene May Lead to New Parkinson’s Treatments: Fly Model

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Over-expressing a fly gene called clueless (clu) can lessen mitochondrial defects in fruit fly models of Parkinson’s disease, a new study reveals.

The results also showed that CLUH, the human equivalent of the fly clueless gene, has a similar function, which may pave the way toward new treatment approaches for Parkinson’s.

“When we modified [clu] in flies, symptoms analogous to Parkinson’s disease improved substantially,” Ming Guo, MD, PhD, a professor at UCLA and co-author of the study, said in a press release.

The study, “Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria,” was published in Nature Communications.

Mitochondria, the so-called “powerhouse of the cell,” are structures that are critical for providing a cell with energy. In Parkinson’s and numerous other neurological conditions, mitochondrial dysfunction is believed to play a key role in the disease’s development and progression. However, the molecular mechanisms that regulate mitochondrial function, both in health and disease states, remain incompletely understood.

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To learn more, a team led by researchers at the UCLA David Geffen School of Medicine first conducted a series of experiments on fruit flies with mutations in the genes PINK1 or parkin. Mutations in the human equivalents of these genes are associated with Parkinson’s, and these mutations lead to Parkinson’s-like mitochondrial defects in the flies.

The team showed that increasing the expression of the clu gene lessened the mitochondrial abnormalities in these fly models of Parkinson’s. Consistently, reducing the expression of the gene made these abnormalities more pronounced. Of note, gene expression is the process by which information in a gene is synthesized to create a protein.

clu [overexpression] rescues mitochondrial and tissue defects … highlighting the potential therapeutic value of manipulating CLUH and [related genes] for the treatment of [Parkinson’s disease],” the team wrote.

Within a cell, one of the key processes that governs mitochondrial health is the balance between fusion — where two mitochondria merge to create one large mitochondria — and fission, where one mitochondria splits into two smaller mitochondria. Further experiments showed that the clu gene helps to promote mitochondrial fission: overexpression of the gene led to the production of many small mitochondria, whereas knocking the gene out resulted in a few, overlarge mitochondria.

Additional experiments revealed that the protein encoded by the clueless gene physically interacts with a protein called Drp1, which is a well-established driver of mitochondrial fission. The interaction prompts Drp1 to be recruited to mitochondria, thus providing a mechanism for how clu overexpression drives mitochondrial fission.

Further experiments in mammalian cells showed that CLUH, the functional equivalent of the fly clueless gene in mammals, has a similar function, promoting mitochondrial fission by interacting with the mammalian Drp1 protein. Also in human cells, the CLUH protein encoded by the gene was shown to promote the production of the Drp1 protein when the gene encoding that protein is “read.”

“Drp1 is the master regulator driving mitochondrial fission, which in turn controls mitochondrial morphology and quality, metabolic homeostasis, and organismal health. In this study, we identified Clu/CLUH as a key evolutionarily conserved regulator of Drp1,” the researchers concluded.

The team suggested that better understanding these pathways may open new approaches to improve mitochondrial impairment in Parkinson’s, which may ultimately pave the way for novel treatment strategies.

“With a critically important pathway such as Drp1, there might be multiple proteins we could use to intervene and ultimately control Parkinson’s disease,” Guo said.

“In the future, we hope to identify a mechanism with such precision that it only affects Parkinson’s disease, so patients can derive maximum benefit,” she added.