β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression

被引:69
作者
Fan, Yuxin
Limprasert, Pornprot
Murray, Ian V. J.
Smith, Annette C.
Lee, Virginia M. -Y.
Trojanowski, John Q.
Sopher, Bryce L.
La Spada, Albert R.
机构
[1] Univ Washington, Med Ctr, Dept Lab Med, Seattle, WA 98195 USA
[2] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA
[3] Univ Washington, Med Ctr, Dept Neurol, Seattle, WA 98195 USA
[4] Univ Washington, Med Ctr, Ctr Neurogenet & Neurotherapuet, Seattle, WA 98195 USA
[5] Univ Penn, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[6] Univ Penn, Inst Aging, Philadelphia, PA 19104 USA
关键词
D O I
10.1093/hmg/ddl242
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as 'Lewy bodies'. As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in 'synucleinopathies'. beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I-125 autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.
引用
收藏
页码:3002 / 3011
页数:10
相关论文
共 34 条
  • [1] A vector for expressing foreign genes in the brains and hearts of transgenic mice
    Borchelt, DR
    Davis, J
    Fischer, M
    Lee, MK
    Slunt, HH
    Ratovitsky, T
    Regard, J
    Copeland, NG
    Jenkins, NA
    Sisodia, SS
    Price, DL
    [J]. GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING, 1996, 13 (06): : 159 - 163
  • [2] The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease
    Clayton, DF
    George, JM
    [J]. TRENDS IN NEUROSCIENCES, 1998, 21 (06) : 249 - 254
  • [3] The biochemistry of Parkinson's disease
    Cookson, MR
    [J]. ANNUAL REVIEW OF BIOCHEMISTRY, 2005, 74 : 29 - 52
  • [4] Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy
    Cuervo, AM
    Stefanis, L
    Fredenburg, R
    Lansbury, PT
    Sulzer, D
    [J]. SCIENCE, 2004, 305 (5688) : 1292 - 1295
  • [5] Viral vectors for gene delivery to the nervous system
    Davidson, BL
    Breakefield, XO
    [J]. NATURE REVIEWS NEUROSCIENCE, 2003, 4 (05) : 353 - 364
  • [6] Animal models of PD: Pieces of the same puzzle?
    Dawson, TM
    Mandir, AS
    Lee, MK
    [J]. NEURON, 2002, 35 (02) : 219 - 222
  • [7] Molecular pathways of neurodegeneration in Parkinson's disease
    Dawson, TM
    Dawson, VL
    [J]. SCIENCE, 2003, 302 (5646) : 819 - 822
  • [8] Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases
    Duda, JE
    Giasson, BI
    Mabon, ME
    Lee, VMY
    Trojanowski, JQ
    [J]. ANNALS OF NEUROLOGY, 2002, 52 (02) : 205 - 210
  • [9] α-Synuclein is phosphorylated by members of the Src family of protein-tyrosine kinases
    Ellis, CE
    Schwartzberg, PL
    Grider, TL
    Fink, DW
    Nussbaum, RL
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (06) : 3879 - 3884
  • [10] Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications
    Farrer, M
    Kachergus, J
    Forno, L
    Lincoln, S
    Wang, DS
    Hulihan, M
    Maraganore, D
    Gwinn-Hardy, K
    Wszolek, Z
    Dickson, D
    Langston, JW
    [J]. ANNALS OF NEUROLOGY, 2004, 55 (02) : 174 - 179