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Home » Conformational Switch Implicated in Neurodegenerative Diseases
Disease Discoveries

Conformational Switch Implicated in Neurodegenerative Diseases

By Will DossMar 23, 2021
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Gabriela Caraveo Piso, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Movement Disorders, was senior author of the study published in PNAS.

Northwestern Medicine scientists have discovered a conformational “switch” that determines the function of the SNARE protein Ykt6, according to a recent study published in Proceedings of the National Academy of the Sciences (PNAS).

This has implications for synucleinopathies, a group of incurable neurodegenerative diseases including Parkinson’s disease, Lewy body dementia and multiple system atrophy, according to Gabriela Caraveo Piso, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Movement Disorders and senior author of the study.

“This is the key to providing either a toxic or a protective outcome,” Caraveo Piso said.

Alpha-synuclein is a misfolded protein that builds up in the brain and is associated with neurological symptoms of synucleinopathies. Previous studies have revealed that one major impact of excess synuclein is interruption of vesicular fusion.

Within each cell, organelles use vesicles to communicate with each other by transporting proteins or lipids in response to specific cellular requirements. In neurons with high levels of alpha-synuclein, the Golgi apparatus is unable to absorb vesicles, causing a variety of downstream problems.

The SNARE proteins are important mediators of vesicular communication and Ykt6 plays an important role in several important vesicular trafficking pathways. However, the upstream regulators of Ykt6 remained mostly unknown, according to Caraveo Piso.

The Caraveo Piso laboratory had previously discovered that excess synuclein caused over-activation of calcineurin, a calcium-dependent phosphatase. In the current study, they used a multidisciplinary approach analyzing yeast, worm and human cell models, searching for interactions between Ykt6 and calcineurin.

The investigators discovered that under high calcineurin activation, the function of Ykt6 is modified. In normal circumstances, Ykt6 plays a protective role against alpha-synuclein toxicity, activating a “program” that helps correct the vesicular trafficking defects caused by alpha-synuclein.

However, high levels of calcineurin cause phosphorylation within Ykt6, driving a conformational— or structure-altering — change that nullifies the protective program.

“Depending on the extent of calcineurin activation, it engages different substrates which is key to achieve either a toxic or protective response,” Caraveo Piso said.

These findings reveal nuances in how Ykt6 and calcineurin impact cellular biological pathways under both normal circumstances and in synucleinopathies and could inform future therapeutic efforts, Caraveo Piso said.

Jeffrey Savas, PhD, assistant professor of Neurology in the Division of Behavioral Neurology, was a co-author of the study.

Neurology and Neuroscience Research
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