title: A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions.
abstract: Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson's disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for 2 months starting at 1 month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured 1 month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 months) NAP administration in a mouse model of synucleinopathy.
authors.affiliation: Departments of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: Caitlin K
authors.initials: CK
authors.lastname: Mulligan
authors.forename: Franziska
authors.initials: F
authors.lastname: Richter
authors.forename: Farzad
authors.initials: F
authors.lastname: Mortazavi
authors.forename: Vincent
authors.initials: V
authors.lastname: Lemesre
authors.forename: Carmen
authors.initials: C
authors.lastname: Frias
authors.forename: Chunni
authors.initials: C
authors.lastname: Zhu
authors.forename: Alistair
authors.initials: A
authors.lastname: Stewart
authors.forename: Illana
authors.initials: I
authors.lastname: Gozes
authors.forename: Bruce
authors.initials: B
authors.lastname: Morimoto
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D019286:Endopeptidase K / Q000378:metabolism; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D009830:Olfactory Bulb / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D010865:Pilot Projects; D013378:Substantia Nigra / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D019286:Endopeptidase K; C425904:davunetide