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LENS Webinar #9 on ‘Elucidating amyloid aggregation mechanisms behind neurodegenerative diseases’ with Emma Sparr (Lund University) & Pau Bernado (CBS/CNRS Montpellier)

LENS Webinar #9,
Global Health Threats:

Elucidating amyloid aggregation mechanisms
behind neurodegenerative diseases

Many debilitating neurodegenerative diseases such as Alzherimers/Parkinsons and Huntington’s are linked to protein misfolding and aggregation into amyloid fibrils and plaques in the brain. This webinar focuses on how neutron scattering techniques can elucidate the structures and steps involved in the aggregation mechanisms to provide crucial information to understand and combat these diseases and to develop better medications.

Emma Sparr (Lund University)
‘Co-assembly of lipids and the amyloid protein alpha-synuclein’
Pau Bernadó (CBS/CNRS Montpellier)
‘Structural Bases of Huntington’s Disease Pathological Threshold.
An Integrative Structural Biology Approach’

4 March 2021, 11:00am CET

Chair: Anne Martel (ILL)

Join via Zoom:

11.00: Emma Sparr | 11.30: Pau Bernadó | 12-12.30: Discussion


Emma SPARR is a professor of physical chemistry and colloidal biology at Lund University, Sweden. She has over many years studied lipid membranes in non-equilibrium conditions, lipid self-assembly and lipid-protein interactions. She finished her PhD in physical chemistry at Lund University in 2001. During her postdoc studies at Utrecht University, she started to study interactions and co-assembly between aggregating amyloid proteins and lipids. Over the last 10 years, she has studied interactions between α-synuclein from Parkinson’s disease, and lipid membranes, focusing on how specific lipids the interaction and co-assembly.

Amyloid aggregates in the brain are found in neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s diseases (AD). The underlying molecular mechanisms for the development of these diseases are not known, although the involved biomolecules have been uncovered. Lipid membranes and amyloid fibrils are dynamic self-assembled structures that co-exist in biology and have a clear influence on each other. The amyloid-forming protein may perturb the structure and integrity of the membrane, and the presence of the membrane may trigger the protein aggregation. Equally important, the co-existence of these dynamic systems of proteins and lipids, respectively, may lead to the formation of co-aggregates  that are lipid-rich or protein-rich. In this talk, I will discuss these different aspects of amyloid-lipid co-assembly in systems containing different lipids and the the protein a-synculein, which has been associated with Parkinson’s disease.

Pau BERNADÓ is a structural biophysicist at the Centre de Biochimie Structurale (CBS) in Montpellier. He is interested in Intrinsically Disordered Proteins (IDPs) from a structural and functional perspective. By combining integrative structural biology approaches (SAS, NMR and computation), his group aims at deciphering the structural bases of disease and signalling events. These last years he has also developed novel chemical biology approaches enabling the atomic resolution investigation of proteins containing low-complexity regions.

Huntington’s disease (HD) is one of nine hereditary neurodegenerative disorders caused by an expansion of CAG triplet repeats beyond a pathological threshold. For HD, this expansion is located in the first exon of the huntingtin gene and results in an abnormally long poly-glutamine (poly-Q) tract within the N-terminus of the huntingtin protein (httex1). When the number of consecutive glutamines exceeds 35 (pathological threshold), the resulting mutant protein forms large cytoplasmic and nuclear aggregates, a hallmark of HD, and causes neuronal degeneration, especially affecting the neurons of the striatum. Aggregation, disease risk and age of onset correlate with the length of the poly-Q homo-repeat.

The origin of a pathological threshold in HD and the other poly-Q related diseases remains poorly understood and different toxicity models for httex1 have been proposed. Httex1 is a flexible protein, precluding its crystallization. In addition, the highly repetitive nature of its sequence difficults high-resolution investigation in solution by Nuclear Magnetic Resonance (NMR). Our group has developed a chemical biology approach that allows for the first time to obtain atomic-resolution information of httex1 independently of the poly-Q length. Using this strategy we have derived structural models of a pathological and a non-patological versions of httex1 with 46 and 16 consecutive glutamines, respectively. The comparison of these models shows that in both cases the protein consists in an equilibrium of helical conformations involving different fractions of the poly-Q. We also show that both poly-Q flanking regions govern the structure of the homo-repeat.

NMR provides accurate information on residue-specific conformational states, but the overall shape and the persistence of the helix remain elusive. In that sense, we have endeavoured a Small-Angle Neutron Scattering (SANS) study to complement our NMR investigations and produce a more complete picture of the httex1 poly-Q structure. For the SANS study we will make use of the Cell-Free protein production, which allows the control of the isotopologues introduced in the protein. This approach enables the segmental labelling of the protein and to highlight specific segments of the protein using contrast variation experiments. Our first SANS experiments and the atomistic simulations showing the power of the approach will be discussed.

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