A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein
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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.
Key WordsParkinson’s disease synucleinopathies mouse model motor behavior α-synuclein aggregation drug testing
This work was supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) P50 grant NS38367 [University of California, Los Angeles (UCLA), Morris K. Udall Parkinson Disease Research Center of Excellence], including a Blueprint supplement to this award, NIH/National Institute of Environmental Health Sciences P01 grant ES016732, RJG Foundation grant 20095024, the Michael J. Fox Foundation, Team Parkinson/Parkinson Alliance, The American Parkinson’s Disease Association, and gifts to the Center for the Study of Parkinson’s Disease at UCLA.
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