Defects in Molecular Chaperones May Help Drive Lewy Body Formation in Parkinson’s, Study Finds

Defects in Molecular Chaperones May Help Drive Lewy Body Formation in Parkinson’s, Study Finds
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Defects in chaperone proteins that interact with alpha-synuclein and work as a type of “molecular bodyguard” may help drive the formation of Lewy bodies, which are a hallmark of Parkinson’s disease.

The findings were published in the journal Nature, in a study titled “Regulation of α-synuclein by chaperones in mammalian cells.”

Lewy bodies are protein aggregates — basically clumps of improperly folded protein — that are often found in the brains of people with Parkinson’s disease. The main protein that forms Lewy bodies is alpha-synuclein. However, what drives alpha-synuclein to form Lewy bodies is an area of ongoing investigation, which may open avenues for the development of treatments.

In this new study, researchers investigated not alpha-synuclein itself but its so-called chaperones. Traditionally, “chaperone” proteins are thought of as proteins that temporarily bind to other proteins to help them fold properly.

The researchers screened dozens of known chaperones in detail to see whether they could interact with alpha-synuclein.

“[W]e have discovered a specific pattern that determines the exact interaction site of [alpha]-synuclein with chaperones,” study co-author Sebastian Hiller, a professor at the University of Basel, said in a press release.

Hiller and colleagues identified six that can interact with alpha-synuclein. Many of these were heat shock proteins, a well-established family of chaperones.

The researchers then set about inhibiting the interaction between alpha-synuclein and its chaperones. They found that, upon blocking this interaction, chaperones could no longer act as “molecular bodyguards” and protect alpha-synuclein, which tended to accumulate in the mitochondria — cells’ powerhouses — where it aggregated, forming clumps of protein that bear a striking resemblance to Lewy bodies.

“Our results establish a master regulatory mechanism of [alpha]-synuclein function and aggregation in mammalian cells,” the researchers said.

While this study doesn’t definitively prove that abnormally functioning chaperones are responsible for Parkinson’s, it suggests that the chaperone system plays a role in the progression of the disease — and, as such, it could be a target for future therapies.

These findings also have implications for the broader biological understanding of what chaperone proteins do.

“With our work, we are questioning the paradigm that the function of chaperones is solely to help proteins to fold into their proper shape,” Hiller said. “Chaperones do far more than just assist in protein folding. They control cellular processes by flexibly interacting with a variety of proteins and accompanying them like a shadow.”

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
Total Posts: 208
Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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