A de novo compound targeting α-synuclein improves deficits in models of Parkinson's disease.
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.
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Wolfgang
W
Wrasidlo
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.|2 San Diego Supercomputer Center, University of California San Diego, La Jolla, CA 92093, USA.
Igor F
IF
Tsigelny
3 Neuropore Therapies, Inc., San Diego, CA 92121, USA.
Diana L
DL
Price
4 Department of Neurology, University of California, Los Angeles, CA, 90095-1769, USA.
Garima
G
Dutta
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Edward
E
Rockenstein
5 MFPL and University of Vienna, Vienna, Austria.
Thomas C
TC
Schwarz
5 MFPL and University of Vienna, Vienna, Austria.
Karin
K
Ledolter
3 Neuropore Therapies, Inc., San Diego, CA 92121, USA.
Douglas
D
Bonhaus
3 Neuropore Therapies, Inc., San Diego, CA 92121, USA.
Amy
A
Paulino
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Simona
S
Eleuteri
2 San Diego Supercomputer Center, University of California San Diego, La Jolla, CA 92093, USA.|6 Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway.
Åge A
ÅA
Skjevik
7 Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
Valentina L
VL
Kouznetsova
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Brian
B
Spencer
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Paula
P
Desplats
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Tania
T
Gonzalez-Ruelas
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Margarita
M
Trejo-Morales
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
Cassia R
CR
Overk
8 EVER Neuropharma, Unterach, Austria.
Stefan
S
Winter
4 Department of Neurology, University of California, Los Angeles, CA, 90095-1769, USA.
Chunni
C
Zhu
4 Department of Neurology, University of California, Los Angeles, CA, 90095-1769, USA.
Marie-Francoise
MF
Chesselet
3 Neuropore Therapies, Inc., San Diego, CA 92121, USA.
Dieter
D
Meier
8 EVER Neuropharma, Unterach, Austria.
Herbert
H
Moessler
5 MFPL and University of Vienna, Vienna, Austria.
Robert
R
Konrat
1 Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA emasliah@UCSD.edu.|9 Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Eliezer
E
Masliah
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000188:drug therapy*; D051844:alpha-Synuclein / Q000187:drug effects*
D000978:Antiparkinson Agents; D051844:alpha-Synuclein
Parkinson’s disease; alpha-synuclein; cellular mechanisms; experimental models; synucleinopathy
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