α-synuclein alters notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice

被引:108
作者
Crews, Leslie [1 ,2 ]
Mizuno, Hideya [1 ]
Desplats, Paula [1 ]
Rockenstein, Edward [1 ]
Adame, Anthony [1 ]
Patrick, Christina [1 ]
Winner, Beate [3 ]
Winkler, Juergen [1 ,3 ]
Masliah, Eliezer [1 ,2 ]
机构
[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
[3] Univ Regensburg, Dept Neurol, D-93053 Regensburg, Germany
关键词
alpha-synuclein; Parkinson's disease; neurogenesis; differentiation; stem cells; dentate gyrus;
D O I
10.1523/JNEUROSCI.0066-08.2008
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Altered expression and mutations in alpha-synuclein (alpha-syn) have been linked to Parkinson's disease (PD) and related disorders. The neurological alterations in PD patients have been associated with degeneration of dopaminergic cells and other neuronal populations. Moreover, recent studies in murine models have shown that alterations in neurogenesis might also contribute to the neurodegenerative phenotype. However, the mechanisms involved and the effects of alpha-syn expression on neurogenesis are not yet clear. To this end, murine embryonic stem (mES) cells were infected with lentiviral (LV) vectors expressing wild-type (WT) and mutant alpha-syn. Compared with mES cells infected with LV-green fluorescent protein (GFP), cells expressing WT and mutant alpha-syn showed reduced proliferation as indicated by lower 5-bromo-2 alpha-deoxyuridine uptake, increased apoptosis, and reduced expression of neuronal markers such as neuron specific enolase and alpha-III tubulin. The alterations in neurogenesis in alpha-syn-expressing mES cells were accompanied by a reduction in Notch-1 and Hairy and enhancer of split-5 (Hes-5) mRNA and protein levels. Moreover, levels of total Notch-1 and Notch intracellular domain (NICD) were lower in mEScells expressing WT and mutant alpha-syn compared with GFP controls. The reduced survival of alpha-syn-expressing mES cells was reverted by overexpressing constitutively active NICD. Similarly, in alpha-syn transgenic mice, the alterations in neurogenesis in the hippocampal subgranular zone were accompanied by decreased Notch-1, NICD, and Hes-5 expression. Together, these results suggest that accumulation of alpha-syn might impair survival of NPCs by interfering with the Notch signaling pathway. Similar mechanisms could be at play in PD and Lewy body disease.
引用
收藏
页码:4250 / 4260
页数:11
相关论文
共 57 条
  • [1] Differentiation of mouse embryonic stem cells into a defined neuronal lineage
    Bibel, M
    Richter, J
    Schrenk, K
    Tucker, KL
    Staiger, V
    Korte, M
    Goetz, M
    Barde, YA
    [J]. NATURE NEUROSCIENCE, 2004, 7 (09) : 1003 - 1009
  • [2] Caspase inhibition decreases cell death in regions of adult neurogenesis
    Biebl, M
    Winner, B
    Winkler, J
    [J]. NEUROREPORT, 2005, 16 (11) : 1147 - 1150
  • [3] Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus
    Breunig, Joshua J.
    Silbereis, John
    Vaccarino, Flora M.
    Sestan, Nenad
    Rakic, Pasko
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (51) : 20558 - 20563
  • [4] Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis
    Brown, J
    Cooper-Kuhn, CM
    Kempermann, G
    Van Praag, H
    Winkler, J
    Gage, FH
    Kuhn, HG
    [J]. EUROPEAN JOURNAL OF NEUROSCIENCE, 2003, 17 (10) : 2042 - 2046
  • [5] Linker histone H1 binds to disease associated amyloid-like fibrils
    Duce, James A.
    Smith, David P.
    Blake, Rachel E.
    Crouch, Peter J.
    Li, Qiao-Xin
    Masters, Colin L.
    Trounce, Ian A.
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 2006, 361 (03) : 493 - 505
  • [6] A Drosophila model of Parkinson's disease
    Feany, MB
    Bender, WW
    [J]. NATURE, 2000, 404 (6776) : 394 - 398
  • [7] Gage FH, 1998, J NEUROBIOL, V36, P249, DOI 10.1002/(SICI)1097-4695(199808)36:2<249::AID-NEU11>3.0.CO
  • [8] 2-9
  • [9] Differential expression and distribution of α-, β-, and γ-synuclein in the developing human substantia nigra
    Galvin, JE
    Schuck, TM
    Lee, VMY
    Trojanowski, JQ
    [J]. EXPERIMENTAL NEUROLOGY, 2001, 168 (02) : 347 - 355
  • [10] Nuclear localization of α-synuclein and its interaction with histones
    Goers, J
    Manning-Bog, AB
    McCormack, AL
    Millett, IS
    Doniach, S
    Di Monte, DA
    Uversky, VN
    Fink, AL
    [J]. BIOCHEMISTRY, 2003, 42 (28) : 8465 - 8471