Shining a light on protein aggregation in Parkinson's disease
Optobiological control of a key protein may reveal the earliest stages of neurodegeneration in mice

Date:
March 22, 2022
Source:
PLOS
Summary:
A novel system to control protein aggregation in a model of
Parkinson's disease may answer longstanding questions about how
the disease begins and spreads, according to a new study. Initial
results suggest that aggregation of the protein alpha-synuclein
plays a critical role in disrupting neuronal homeostasis and
triggering neurodegeneration.



FULL STORY ==========================================================================
A novel system to control protein aggregation in a model of Parkinson's
disease may answer longstanding questions about how the disease begins and spreads, according to a new study published March 9 in the open-access
journal PLOS Biology by Abid Oueslati of Laval University, Quebec,
Canada, and colleagues.

Initial results suggest that aggregation of the protein alpha-synuclein
plays a critical role in disrupting neuronal homeostasis and triggering neurodegeneration.


========================================================================== Parkinson's disease is a neurodegenerative disorder, marked clinically by tremor, stiffness, and slowed movements, as well as a host of nonmotor symptoms. Within affected neurons, molecules of a protein called alpha- synuclein can be seen to clump together, forming characteristic aggregates called Lewy bodies. But it has been hard to answer whether alpha-synuclein aggregation contributes to disease development or progression, and
when it may act in the toxic disease cascade, or whether instead the
aggregates are innocent bystanders to some other malevolent 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 in
either time or space.

To address that problem, the authors turned to optobiology, a technique in which a protein of interest is fused to another protein that changes its 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 protein 2,
from a mustard plant.

They found that when light of the correct wavelength fell on the
mustard protein, its conformational change triggered aggregation of its alpha-synuclein partner.

The aggregates that formed were reminiscent of Lewy bodies in multiple important ways, including that they included several other key proteins
besides 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 diseases of
misfolded proteins. The aggregates induced dislocation of multiple
cellular organelles, as Lewy bodies have been recently reported to do
as well. They also induced misfolding in alpha- synuclein molecules not attached to the cryptochrome protein, mimicking the prion-like spread
of aggregation seen with alpha-synuclein in the diseased brain and
animal models.

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

"Our results demonstrate the potential of this optobiological system to reliably and controllably induce formation of Lewy body-like aggregations
in model systems, in order to better understand the dynamics and timing of
Lewy body formation and spread, and their contribution to the pathogenesis
of Parkinson's disease," Oueslati said.

Oueslati adds, "How do alpha-synuclein aggregates contribute to neuronal
damage in Parkinson's disease? To help address this question, we developed
a new optogenetic-based experimental model allowing for the induction
and real-time monitoring of alpha-synuclein clustering in vivo."

========================================================================== Story Source: Materials provided by PLOS. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Morgan Be'rard, Razan Sheta, Sarah Malvaut, Raquel Rodriguez-Aller,
Maxime Teixeira, Walid Idi, Roxanne Turmel, Melanie Alpaugh,
Marilyn Dubois, Manel Dahmene, Charleen Salesse, Je'ro^me
Lamontagne-Proulx, Marie-Kim St-Pierre, Omid Tavassoly, Wen Luo,
Esther Del Cid-Pellitero, Raza Qazi, Jae-Woong Jeong, Thomas
M. Durcan, Luc Vallie`res, Marie-Eve Tremblay, Denis Soulet,
Martin Le'vesque, Francesca Cicchetti, Edward A.

Fon, Armen Saghatelyan, Abid Oueslati. A light-inducible protein
clustering system for in vivo analysis of a-synuclein aggregation
in Parkinson disease. PLOS Biology, 2022; 20 (3): e3001578 DOI:
10.1371/ journal.pbio.3001578 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220322145738.htm

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