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

被引：68

作者：

Fleming, Sheila M. ^{[1
,2
]}

Mulligan, Caitlin K. ^{[1
,2
]}

Richter, Franziska ^{[1
,2
]}

Mortazavi, Farzad ^{[1
,2
]}

Lemesre, Vincent ^{[1
,2
]}

Frias, Carmen ^{[1
,2
]}

Zhu, Chunni ^{[1
,2
]}

Stewart, Alistair ^{[4
]}

Gozes, Illana ^{[3
,4
]}

Morimoto, Bruce ^{[4
]}

Chesselet, Marie-Francoise ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA

[3] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel

[4] Allon Therapeut Inc, Vancouver, BC V6B 2S2, Canada

来源：

MOLECULAR AND CELLULAR NEUROSCIENCE | 2011年 / 46卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Parkinson's disease; Sensorimotor function; Substantia nigra; Olfaction; Olfactory bulb; REDUCES TAU HYPERPHOSPHORYLATION; TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; PROTEIN; BRAIN; ACCUMULATION; NEUROPROTECTION; ASSOCIATION; PERFORMANCE; IMPAIRMENT;

D O I：

10.1016/j.mcn.2010.12.011

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Abnormal accumulation of alpha-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson's disease (PD). Genetic mutations and multiplication of alpha-synuclein cause familial forms of PD and polymorphisms in the alpha-synuclein gene are associated with PD risk. Overexpression of alpha-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 alpha-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 alpha-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 alpha-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of alpha-synuclein pathology following administration of a short term (2 months) NAP administration in a mouse model of synucleinopathy. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：597 / 606

页数：10

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