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Neurotherapeutics. 2017 Oct;14(4):1107-1119. doi: 10.1007/s13311-017-0544-9.

A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein.

Author information

1
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
2
Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
3
Institute of Organic Chemistry, University of Duisburg-Essen, Essen, Germany.
4
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu.
5
Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu.
6
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu.
7
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. mchesselet@mednet.ucla.edu.
8
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu.
9
Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu.
10
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. gbitan@mednet.ucla.edu.

Abstract

Aberrant accumulation and self-assembly of α-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic α-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.

KEYWORDS:

Parkinson’s disease; drug testing; motor behavior; mouse model; synucleinopathies; α-synuclein aggregation

PMID:
28585223
PMCID:
PMC5722755
[Available on 2018-10-01]
DOI:
10.1007/s13311-017-0544-9
[Indexed for MEDLINE]

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