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Shedding light on protein aggregation in Par


image: The image shows a human iPSC-derived neuron overexpressing the LIPA-α-synuclein construct. Upon exposure to light, we observe the formation of LIPA-α-synuclein aggregates (green) in the soma and neuronal processes (MAP2; magenta).
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Credit: Maxime Teixeira (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)

A new system to control protein aggregation in a model of Parkinson’s disease could answer long-standing questions about how the disease begins and spreads, according to a new study published March 9.and in the open access journal PLOS Biology by Abid Oueslati of Laval University, Quebec, Canada, and his colleagues. The first results suggest that the aggregation of the protein alpha-synuclein plays an essential role in the disruption of neuronal homeostasis and the triggering of neurodegeneration.

Parkinson’s disease is a neurodegenerative disease, clinically marked by tremors, stiffness and slowed movements, as well as a host of non-motor symptoms. In affected neurons, molecules of a protein called alpha-synuclein can be seen clumping together, forming characteristic aggregates called Lewy bodies. But it has been unclear whether alpha-synuclein aggregation contributes to disease development or progression, and when it may act in the toxic disease cascade, or whether the aggregates are innocent bystanders. from another malicious process, or are even protective. These elements have been difficult to determine, in part because aggregation in cellular and animal models has not been controllable over time or space.

To solve this problem, the authors turned to optobiology, a technique in which a protein of interest is fused to another protein that changes conformation in response to light, allowing the behavior of the target protein to be manipulated. selectively and reversibly. Here, the authors fused alpha-synuclein to a protein known as cryptochrome 2 protein, from a mustard plant. They found that when light of the correct wavelength fell on the mustard protein, its conformational change triggered the aggregation of its partner alpha-synuclein.

The aggregates that formed were reminiscent of Lewy bodies in several important ways, including that they included several other key proteins in addition to alpha-synuclein found in Lewy bodies in people with Parkinson’s disease, and that the alpha-synuclein in the aggregates adopted the characteristic beta-sheet conformation seen in many misfolded protein diseases. The aggregates induced the dislocation of several cell organelles, as Lewy bodies have recently been reported to do as well. They also induced misfolding of alpha-synuclein molecules not attached to the cryptochrome protein, mimicking the spread of prion-like aggregation seen with alpha-synuclein in diseased brain and animal models.

Finally, the authors delivered the alpha-synuclein-cryptochrome fusion protein genes to mice directly into the substantia nigra, the brain structure most affected by Parkinson’s disease, and surgically placed an optical fiber to deliver of light to the targeted cells. Light treatment resulted in the formation of alpha-synuclein aggregates, neurodegeneration, disruption of calcium activity in downstream neuronal targets, and Parkinsonian-like motor deficits.

“Our results demonstrate the potential of this optobiological system to reliably and controlled induce the formation of Lewy body-like aggregations in model systems, to better understand the dynamics and timing of body formation and propagation. de Lewy, and their contribution to the pathogenesis of Parkinson’s disease. illness,” Oueslati said.

Oueslati adds: “How do alpha-synuclein aggregates contribute to neuronal damage in Parkinson’s disease? To help answer this question, we have developed a novel optogenetic-based experimental model allowing the induction and real-time monitoring of alpha-synuclein clustering in vivo.


In your coverage, please use this URL to provide access to the article available for free in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001578

Quote: Bérard M, Sheta R, Malvaut S, Rodriguez-Aller R, Teixeira M, Idi W, et al. (2022) A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson’s disease. PLoS Biol 20(3): e3001578. https://doi.org/10.1371/journal.pbio.3001578

Author countries: Canada, United States, Republic of Korea

Funding: This work was supported by Parkinson Society Canada, the CHU de Québec Foundation, and Canadian Institutes of Health Research (CIHR) grants to AO. AO was supported by the Junior1 and Junior 2 salary grants from the Fonds de Recherche du Québec – Santé (FRQS) and the Parkinson Society of Quebec. The in vivo Ca2+ imaging experiments were supported by the Canadian Institutes of Health Research (CIHR) grant to AS. MB was supported by scholarships from the CHU de Québec Foundation, the Laval University Faculty of Medicine (Pierre J. Durant Doctoral Recruitment Scholarship) and the FRQS. FC is the recipient of a research chair from the Fonds de Recherche du Québec en Santé (FRQS) and has received funding from the Canadian Institutes of Health Research (CIHR). The master’s is supported by CIHR and FRQS postdoctoral fellowships. EAF is supported by a CIHR Foundation grant (FDN-154301) and a Canada Research Chair (Tier 1) in Parkinson’s disease. MKSP was supported by a Frederick Banting and Charles Best Canada Graduate Scholarship and an FRQS Doctoral Training Fellowship. MET is a Tier 2 Canada Research Chair in Neurobiology of Aging and Cognition. TMD is supported by funds from McGill Healthy Brains for Healthy lives and a CIHR project grant (PJT–169095). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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