Allosteric Modulation of Pathological Ataxin‐3 Aggregation: A Path to Spinocerebellar Ataxia Type‐3 Therapies
Year: 2025
Type: article
Abstract: Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) repeat in ataxin-3 (Atx3) for which no disease-modifying therapies are available. The presence of protein inclusions enriched in polyQ-expanded Atx3 in neurons suggests that inhibiting its self-assembly may provide targeted therapies. Here, it is demonstrated that the supramolecular tweezer CLR01 binds to a lysine residue on a positively charged patch of the Atx3 catalytic Josephin domain, decreasing conformational fluctuations of the distal helical hairpin, without altering its ubiquitin hydrolase activity. This reduces exposure of the aggregation-prone region that initiates Atx3 self-assembly, ultimately delaying Atx3 amyloid fibril formation and reducing the secondary nucleation rate, a process linked to fibril proliferation and toxicity. CLR01's effects translate into the reversal of synapse loss in SCA3 cultured cortical neuron model, improve locomotor function in a Caenorhabditis elegans SCA3 model, and delay disease onset with reduced severity of motor symptoms in a SCA3 mouse model. These insights reveal a novel allosteric site for developing CLR01-inspired therapies targeting pathological aggregation while preserving essential functional sites. They also highlight that targeting allosteric sites in amyloid-forming proteins may provide new opportunities for safe therapeutic strategies for various protein misfolding disorders.
Source: Advanced Science
Authors: Alexandra Silva, Sara Duarte‐Silva, Pedro M. Martins, Beatriz Rodrigues, Débora Serrenho, Daniela Vilasboas‐Campos, Andreia Teixeira‐Castro, Julio Vieyto‐Nuñez, Joel Mieres‐Perez, Francisco Figueiredo, Martyna Podlasiak, Tatiana Van‐der‐Kellen, Joana Fraga, James Noble, Carter Lantz, Niki Sepanj, Daniela Monteiro‐Fernandes, Sara Guerreiro, Andreia Neves‐Carvalho, Joana Pereira‐Sousa, Frank‐Gerrit Klärner, Thomas Schrader, Joseph A. Loo, Annalisa Pastore, Elsa Sanchez‐Garcia, Gal Bitan, Ana Luísa Carvalho, Patrícia Maciel, Sandra Macedo‐Ribeiro
Institutions: Universidade do Porto, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Instituto de Biologia Molecular e Celular, University of Minho, Centro de Neurociências e Biologia Celular, Centro de Inovação em Biomedicina e Biotecnologia, University of Coimbra, TU Dortmund University, King's College London, University of California, Los Angeles, University of Duisburg-Essen
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
Funders: Foundation for the National Institutes of Health, U.S. Department of Energy, National Ataxia Foundation, Amyloidosis Foundation, Deutsche Forschungsgemeinschaft, National Institutes of Health, Fundação para a Ciência e a Tecnologia, National Institute on Aging, H2020 Spreading Excellence and Widening Participation
Awards: ICVS/3B’s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Biodegradaveis e Biomiméticos, Instituto de Investigação e Inovação em Saúde, G1272248415, G1516346500, BetaMarker: Biomarkers of Beta Cell Stress in Type 1 Diabetes, G1565084568, EXC 2033: RESOLV (Ruhr Explores Solvation), G1763632427, G198576669, G199205490, G2195151728, ICVS/3B’s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Biodegradaveis e Biomiméticos, G274347230, Study of cerebellar circuit dysfunction in Machado-Joseph disease, G3616518640, High-Resolution Ion Mobility Mass Spectrometer, ICVS/3B’s - Laboratório Associado, Instituto de Ciências da Vida e da Saúde / Grupo de Investigação em Biomateriais, Biodegradaveis e Biomiméticos, G3840324753, Chemogenomics screening for novel therapeutic target identification in a C. elegans model of Machado-Joseph disease, G5224927334, G5356874719, G5454278309, G5495514737, Excellence Hub on Phase Transitions in Aging and Age-Related Disorders, G5852996515, G5990751553, G599083982, Compute Cluster, G6322190656, Targeting diffusible oligomers of alpha-synuclein and ataxin-3 as a drug repurposing opportunity for the treatment of Parkinsons disease and Machado-Joseph disease, Integration of behavior and neuronal physiology in a mouse model of Rett Syndrome: a particular focus on serotonergic system modulation, Nanostructures in the Ataxin-3 fibrillization pathway: Implications for toxicity in Machado-Joseph Disease, G6940391506, G6997658380, G781353838, Desenvolvimento de ferramenta moleculares para a doença de Machado-Joseph: moduladores de conformações tóxicas em proteínas com poliglutaminas., UCLA-DOE INSTITUTE FOR GENOMICS AND PROTEOMICS, SFB 1430: Molekulare Mechanismen von Zellzustandsübergängen, Misfolded protein clearance enhancers for Alzheimers therapy, G862925997, G894242580, CENTER FOR GENOMICS AND PROTEOMICS RESEARCH PROGRAM, G9000029838
OpenAlex ID: W4416733434