A new mutation behind synucleinopathies

Date:
April 29, 2022
Source:
Ecole Polytechnique Fe'de'rale de Lausanne
Summary:
Scientists have carried out an extensive study of a newly discovered
mutation that can uncover new insights into the molecular basis
of pathology formation in a family of disorders that includes Lewy
body dementia and Parkinson's disease.



FULL STORY ========================================================================== Parkinson's disease and Lewy body dementia belong to a family of neurodegenerative disorders called synucleinopathies because they are
caused by the pathological accumulation of protein alpha-synuclein into structures called Lewy bodies and Lewy neurites in the brain.


==========================================================================
In a healthy brain, alpha-synuclein is found in synapses as distinct
proteins called monomers. But various mutations of the gene that encodes alpha-synuclein can cause the protein to clump together and form larger oligomers and even larger fibrils.

Scientists have identified and mapped out a lot of mutations of the
alpha- synuclein gene that lead to synucleinopathies, with many studies, including work from the Lashuel lab, showing the mutations may also act
through distinct mechanisms, leading to the same pathology. Although
rare, studying these mutations has led to important insights and helped
unmask different mechanisms that contribute to neurodegeneration and
the development of Parkinson's disease.

A novel mutation But in 2020, a study reported a new mutation of the alpha-synuclein gene in a patient with Lewy body dementia and an atypical degeneration of the frontal and temporal lobes. The mutation substitutes
the amino acid glutamate (E) with a glutamine (Q) at the 83rd position
of the protein's amino acid sequence - - which is why the mutation
is called E83Q. What distinguishes this mutation from all previously
identified mutations is that it lies in the middle of the domain that
regulates alpha-synuclein normal functions (interaction with membranes)
and drives aggregation and pathology formation initiation.

Exploring a new path "I was intrigued by the unique position of this
mutation and the fact that the E83Q mutation carrier showed severe Lewy
body pathology in the cortical and hippocampal regions of the brain
than the usual substantia nigra which tends to be majorly affected
in Parkinson's disease," says Hilal Lashuel at EPFL's School of Life
Sciences.



========================================================================== Lashuel adds: "These observations suggested that the new mutation may
influence alpha-synuclein's structure, aggregation, and pathogenicity
through mechanisms distinct from those of other mutations and could help
us uncover novel mechanisms linking alpha-synuclein to neurodegeneration
and pathology formation in Parkinson's disease." The scientists
collaborated with the groups of Markus Zweckstetter at DZNE in Germany
and Frank Sobott at the University of Leeds. They applied a battery
of biochemical, structural, and imaging approaches to dissect how this
mutation modifies the structure of the different forms of alpha-synuclein
and its aggregation properties in vitro. Next, they used a combination
of cellular models of Lewy body formation to determine how the E83Q
mutation influences various aspects of alpha-synuclein associated with
its normal function and pathology.

Their in vitro studies showed that this mutation not only increased dramatically the rate of alpha-synuclein aggregation but also formed
aggregates with structural and morphological signatures that are distinct
from those seen with the normal protein. "This was exciting since recent studies have shown that aggregates of different structures exhibit
differences in their ability to induce pathology and spreading in mouse
models of PD and could possibly explain the clinical heterogeneity of Parkinson's disease and other neurodegenerative diseases," says Senthil
T. Kumar, one of the study's first authors.

To determine if these structural differences are sufficient to translate
into differences in pathology formation and toxicity, the researchers
compared the ability of E83Q and the normal alpha-synuclein protein to
induce pathology formation in a neuronal model of Lew body formation and neurodegeneration that was developed in the Lashuel lab and is widely
used to identify novel targets and test new alpha-synuclein targeting therapies.

"In the neuronal seeding model of Lewy body formation, the E83Q mutation
not only dramatically increased the seeding activity and the formation
of Lewy body-like inclusions, but it also led to the formation of
multiple aggregates with diverse morphological features -- very similar
to the diversity of alpha- synuclein pathology seen in the brains of
patients with Parkinson's disease," says Anne-Laure Mahul-Mellier,
the study's other first author. "We were thrilled to see that we can
achieve this in our Lewy-body in a dish model." "Our findings support
a central role of alpha-synuclein in the development of PD and other synucleinopathies and demonstrate that variations in the structural
properties of alpha-synuclein aggregates could contribute to the neuropathological and clinical heterogeneity of synucleiniopathies,"
says Lashuel. "Thus, emphasizing the critical importance of using
disease models that reproduce to the extent possible the diversity of
the human pathology and therapies capable of targeting the diversity of pathological alpha-synuclein species." As a next step, Lashuel's group
will validate these findings in animal models using material isolated
from the affected patient, and will further investigate whether this
mutation also influences the normal functions of alpha-synuclein.


========================================================================== Story Source: Materials provided by
Ecole_Polytechnique_Fe'de'rale_de_Lausanne. Original written by Nik Papageorgiou. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Senthil T. Kumar, Anne-Laure Mahul-Mellier, Ramanath Narayana Hegde,
Gwladys Rivie`re, Rani Moons, Alain Iba'n~ez de Opakua, Pedro
Magalha~es, Iman Rostami, Sonia Donzelli, Frank Sobott, Markus
Zweckstetter, Hilal A.

Lashuel. A NAC domain mutation (E83Q) unlocks the
pathogenicity of human alpha-synuclein and recapitulates its
pathological diversity. Science Advances, 2022; 8 (17) DOI:
10.1126/sciadv.abn0044 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220429144852.htm

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