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The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy.

Abstract

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder that has no cure and very limited treatment options. MSA is characterized by deposition of fibrillar α-synuclein (α-syn) in glial cytoplasmic inclusions in oligodendrocytes. Similar to other synucleinopathies, α-syn self-assembly is thought to be a key pathologic event and a prominent target for disease modification in MSA. Molecular tweezers are broad-spectrum nanochaperones that prevent formation of toxic protein assemblies and enhance their clearance. The current lead compound, CLR01, has been shown to inhibit α-syn aggregation but has not yet been tested in the context of MSA. To fill this gap, here, we conducted a proof-of-concept study to assess the efficacy of CLR01 in remodeling MSA-like α-syn pathology in the PLP-α-syn mouse model of MSA. Six-month-old mice received intracerebroventricular CLR01 (0.3 or 1 mg/kg per day) or vehicle for 32 days. Open-field test revealed a significant, dose-dependent amelioration of an anxiety-like phenotype. Subsequently, immunohistochemical and biochemical analyses showed dose-dependent reduction of pathological and seeding-competent forms of α-syn, which correlated with the behavioral phenotype. CLR01 treatment also promoted dopaminergic neuron survival in the substantia nigra. To our knowledge, this is the first demonstration of an agent that reduces formation of putative high-molecular-weight oligomers and seeding-competent α-syn in a mouse model of MSA, supporting the view that these species are key to the neurodegenerative process and its cell-to-cell progression in MSA. Our study suggests that CLR01 is an attractive therapeutic candidate for disease modification in MSA and related synucleinopathies, supporting further preclinical development.

Authors+Show Affiliations

Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.Department of Neurology, University of California, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.Department of Neurology, University of California, Los Angeles, CA, USA.Department of Neurology, University of California, Los Angeles, CA, USA.Department of Neurology, University of California, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, CA, USA.Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.Institute of Chemistry, University of Duisburg-Essen, Essen, Germany.Institute of Chemistry, University of Duisburg-Essen, Essen, Germany.Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria.Institute of Chemistry, University of Duisburg-Essen, Essen, Germany.Institute of Chemistry, University of Duisburg-Essen, Essen, Germany.Department of Neurology, University of California, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, CA, USA. Electronic address: gbitan@mednet.ucla.edu.Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Austria. Electronic address: nadia.stefanova@i-med.ac.at.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31319154

Citation

Herrera-Vaquero, Marcos, et al. "The Molecular Tweezer CLR01 Reduces Aggregated, Pathologic, and Seeding-competent Α-synuclein in Experimental Multiple System Atrophy." Biochimica Et Biophysica Acta. Molecular Basis of Disease, 2019.
Herrera-Vaquero M, Bouquio D, Kallab M, et al. The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy. Biochim Biophys Acta Mol Basis Dis. 2019.
Herrera-Vaquero, M., Bouquio, D., Kallab, M., Biggs, K., Nair, G., Ochoa, J., ... Stefanova, N. (2019). The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy. Biochimica Et Biophysica Acta. Molecular Basis of Disease, doi:10.1016/j.bbadis.2019.07.007.
Herrera-Vaquero M, et al. The Molecular Tweezer CLR01 Reduces Aggregated, Pathologic, and Seeding-competent Α-synuclein in Experimental Multiple System Atrophy. Biochim Biophys Acta Mol Basis Dis. 2019 Jul 15; PubMed PMID: 31319154.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The molecular tweezer CLR01 reduces aggregated, pathologic, and seeding-competent α-synuclein in experimental multiple system atrophy. AU - Herrera-Vaquero,Marcos, AU - Bouquio,Danielle, AU - Kallab,Martin, AU - Biggs,Karl, AU - Nair,Gayatri, AU - Ochoa,Jessica, AU - Heras-Garvin,Antonio, AU - Heid,Christian, AU - Hadrovic,Inesa, AU - Poewe,Werner, AU - Wenning,Gregor K, AU - Klärner,Frank-Gerrit, AU - Schrader,Thomas, AU - Bitan,Gal, AU - Stefanova,Nadia, Y1 - 2019/07/15/ PY - 2019/01/22/received PY - 2019/07/09/revised PY - 2019/07/12/accepted PY - 2019/7/19/entrez PY - 2019/7/19/pubmed PY - 2019/7/19/medline KW - Aggregation KW - Glial cytoplasmic inclusions KW - Mouse model KW - Multiple system atrophy KW - Neuropathology KW - Oligomerization KW - Seeding KW - Synucleinopathy JF - Biochimica et biophysica acta. Molecular basis of disease JO - Biochim Biophys Acta Mol Basis Dis N2 - Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder that has no cure and very limited treatment options. MSA is characterized by deposition of fibrillar α-synuclein (α-syn) in glial cytoplasmic inclusions in oligodendrocytes. Similar to other synucleinopathies, α-syn self-assembly is thought to be a key pathologic event and a prominent target for disease modification in MSA. Molecular tweezers are broad-spectrum nanochaperones that prevent formation of toxic protein assemblies and enhance their clearance. The current lead compound, CLR01, has been shown to inhibit α-syn aggregation but has not yet been tested in the context of MSA. To fill this gap, here, we conducted a proof-of-concept study to assess the efficacy of CLR01 in remodeling MSA-like α-syn pathology in the PLP-α-syn mouse model of MSA. Six-month-old mice received intracerebroventricular CLR01 (0.3 or 1 mg/kg per day) or vehicle for 32 days. Open-field test revealed a significant, dose-dependent amelioration of an anxiety-like phenotype. Subsequently, immunohistochemical and biochemical analyses showed dose-dependent reduction of pathological and seeding-competent forms of α-syn, which correlated with the behavioral phenotype. CLR01 treatment also promoted dopaminergic neuron survival in the substantia nigra. To our knowledge, this is the first demonstration of an agent that reduces formation of putative high-molecular-weight oligomers and seeding-competent α-syn in a mouse model of MSA, supporting the view that these species are key to the neurodegenerative process and its cell-to-cell progression in MSA. Our study suggests that CLR01 is an attractive therapeutic candidate for disease modification in MSA and related synucleinopathies, supporting further preclinical development. SN - 1879-260X UR - https://www.unboundmedicine.com/medline/citation/31319154/The_molecular_tweezer_CLR01_reduces_aggregated,_pathologic,_and_seeding-competent_α-synuclein_in_experimental_multiple_system_atrophy L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(19)30230-3 DB - PRIME DP - Unbound Medicine ER -