A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease

  • Brain. 2016 Dec;139(Pt 12):3217-3236. doi: 10.1093/brain/aww238.
Wolfgang Wrasidlo  1 ,  Igor F Tsigelny  1  2 ,  Diana L Price  3 ,  Garima Dutta  4 ,  Edward Rockenstein  1 ,  Thomas C Schwarz  5 ,  Karin Ledolter  5 ,  Douglas Bonhaus  3 ,  Amy Paulino  3 ,  Simona Eleuteri  1 ,  Åge A Skjevik  2  6 ,  Valentina L Kouznetsova  7 ,  Brian Spencer  1 ,  Paula Desplats  1 ,  Tania Gonzalez-Ruelas  1 ,  Margarita Trejo-Morales  1 ,  Cassia R Overk  1 ,  Stefan Winter  8 ,  Chunni Zhu  4 ,  Marie-Francoise Chesselet  4 ,  Dieter Meier  3 ,  Herbert Moessler  8 ,  Robert Konrat  5 ,  Eliezer Masliah  9  10
Affiliations
  • 1. 1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
  • 2. 2 San Diego Supercomputer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • 3. 3 Neuropore Therapies, Inc., San Diego, CA 92121, USA.
  • 4. 4 Department of Neurology, University of California, Los Angeles, CA, 90095-1769, USA.
  • 5. 5 MFPL and University of Vienna, Vienna, Austria.
  • 6. 6 Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway.
  • 7. 7 Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
  • 8. 8 EVER Neuropharma, Unterach, Austria.
  • 9. 1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA [email protected].
  • 10. 9 Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
PMID: 27679481 DOI: 10.1093/brain/aww238
Abstract

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and Other synucleinopathies.

Keywords
Parkinson’s disease; alpha-synuclein; cellular mechanisms; experimental models; synucleinopathy.
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