Marie-Françoise Chesselet, M.D., Ph.D.
University of California, Los Angeles

Marie-Françoise Chesselet is the Charles H. Markham Professor of Neurology and distinguished Professor in the Department of Neurology and the Department of Neurobiology at UCLA. After receiving her M.D. and Ph.D. degrees in Paris, France, she held research positions in France and faculty positions at the Medical College of Pennsylvania and the University of Pennsylvania, before joining UCLA in 1996. At UCLA, Chesselet chaired the Department of Neurobiology from 2002 to 2013 and is currently the Director of the Integrative Center for Neural Repair, which includes the Center for the Study of Parkinson’s Disease at UCLA she created in 1998. She has directed the NIH-funded UCLA UDALL Center for Parkinson’s disease research (NINDS; 1998-2013) and UCLA Center for Gene Environment in Parkinson’s Disease (NIEHS; 2002-2014), and the UCLA Advanced Center for Parkinson’s Disease Research of the American Parkinson Disease Association since 1998. Chesselet has directed graduate programs at the University of Pennsylvania and UCLA and has directed the NINDS-funded Training Program in Neural Repair since 1998. Her laboratory conducts research on the molecular mechanisms of disorders of the basal ganglia and new treatments for Parkinson’s and Huntington’s diseases. Her work is supported by the NIH, the Department of Defense, the Michael J. Fox Foundation, CIRM, and biopharmaceutical companies. Chesselet is a Fellow of the American Association for the Advancement of Science and the Chair-elect of its section on Neuroscience. She serves on the National Advisory Environmental Health Sciences Council (NIEHS Council).

Our laboratory has assessed the efficacy of CLR01 in improving behavioral and pathological deficits in a well-characterized mouse model of synucleopathies, mice over-expressing full-length, wild-type, human α-synuclein under the Thy1 promoter (Rockenstein et al., 2002). These mice show α-synuclein aggregates throughout the brain, regional inflammation (Watson et al., 2012), progressive motor deficits from as early as 2 months of age (Fleming et al., 2004), non-motor deficits in domains also affected in Parkinson’s disease (Chesselet et al., 2012, McDowell et al., 2014) and a loss of striatal dopamine by 14 months of age (Lam et al., 2011), indicating that they provide a useful model of pre-manifest Parkinson’s disease, with a range of end point measures that provide a high power to detect drug effects (Fleming et al., 2011, Richter et al., 2014).

In a joint study with the Bitan group, we found that treatment of the mice for one month with CLR01 improved motor and coordination deficits (Richter et al., 2017). Interestingly, this improvement correlated with a reduction of the soluble form of α-synuclein in the striatum, where the dopamine is secreted, without decreasing the amount of insoluble α-synuclein. The soluble form of α-synuclein is though to be the most toxic form, whereas the insoluble form is what is found in Lewy bodies. Our findings in this study suggest that reducing the soluble form may be sufficient for disease-modifying therapy for Parkinson’s disease whereas reducing Lewy bodies may not be necessary.

References

Chesselet M-F, Richter F, Zhu C, Magen I, Watson M, Subramaniam S. A Progressive Mouse Model of Parkinson’s Disease: The Thy1-aSyn (“Line 61”) Mice. Neurotherapeutics. 2012:1-18.

Fleming SM, Mulligan CK, Richter F, Mortazavi F, Lemesre V, Frias C, et al. A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing α-synuclein shows improvement in motor function and reduction of α-synuclein inclusions. Mol Cell Neurosci. 2011 Mar;46(3):597-606.

Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human α-synuclein. J Neurosci. 2004 Oct 20;24(42):9434-40.

Lam HA, Wu N, Cely I, Kelly RL, Hean S, Richter F, et al. Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein. Journal of Neuroscience Res. 2011 Jul;89(7):1091-102.

McDowell KA, Shin D, Roos KP, Chesselet MF. Sleep Dysfunction and EEG Alterations in Mice Overexpressing α-Synuclein. Journal of Parkinson’s disease. 2014 May 27.

Richter F, Gao F, Medvedeva V, Lee P, Bove N, Fleming SM, et al. Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by α-synuclein overexpression in nigrostriatal dopaminergic neurons. Neurobiol Dis. Sep 2014;69:263–275.

F Richter, I Magen, P Lee, S Subramaniam, J Hayes, A Attar, C Zhu, N Franich, N Bove, K De La Rosa, J Kwong, F-G Klärner, T Schrader, M- F Chesselet, and G Bitan (2017) A molecular tweezer ameliorates motor deficits in mice overexpressing α-synuclein. Neurotherapeutics, in press. E-pub ahead of print, DOI: 10.1007/s13311-017-0544-9.

Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, et al. Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. Journal of Neuroscience Res. 2002 Jun 1;68(5):568-78.

Watson MB, Richter F, Lee SK, Gabby L, Wu J, Masliah E, et al. Regionally-specific microglial activation in young mice over-expressing human wildtype α-synuclein. Exp Neurol. 2012 Oct;237(2):318-34.