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 9th 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.”
Reference:
Bérard M, Sheta R, Malvaut S, et al. A light-inducible protein clustering
system for in vivo analysis of α-synuclein aggregation in Parkinson disease.
PLOS Biology. 2022;20(3):e3001578.
DOI: 10.1371/journal.pbio.3001578