2. Academic Validation
  3. A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease

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

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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