Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies

被引:68
作者
Lee, SS
Kim, YM
Junn, E
Lee, G
Park, KH
Tanaka, M
Ronchetti, RD
Quezado, MM
Mouradian, MM
机构
[1] NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA
[2] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA
关键词
alpha-synuclein; Parkinson; proliferation; MAPK; cell cycle; synucleinopathy; Alzheimer; PC12; cells;
D O I
10.1016/S0197-4580(02)00196-3
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
alpha-Synuclein is a presynaptic protein that accumulates abnormally in Lewy bodies of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Its physiological function and role in neuronal death remain poorly understood. Recent immunohistochemical studies suggest that cell cycle-related phenomena may play a role in the pathogenesis of Alzheimer's disease and perhaps other neurodegenerative disorders. In this investigation, we examined the effects of alpha-synuclein expression levels on cell cycle indices in PC12 cells engineered to conditionally induce alpha-synuclein expression upon withdrawal of doxycycline. Over-expression of alpha-synuclein resulted in enhanced proliferation rate and enrichment of cells in the S phase of the cell cycle. This was associated with increased accumulation of the mitotic factor cyclin B and down-regulation of the tumor suppressor retinoblastoma 2. Additionally, ERK1/2, key molecules in proliferation signaling, were highly phosphorylated. Immunohistochemical studies on postmortem brains revealed intense cyclin B immunoreactivity in Lewy bodies in cases with DLB and to a lesser extent in PD. We propose that elevated expression of alpha-synuclein causes changes in cell cycle regulators through ERK activation leading to apoptosis of postmitotic neurons. These changes in cell cycle proteins are also associated with ectopic expression of cyclin B in Lewy bodies. (C) 2002 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:687 / 696
页数:10
相关论文
共 82 条
[1]   DIFFERENTIAL EFFECT OF NGF AND EGF ON ERK IN NEURONALLY DIFFERENTIATED PC12 CELLS [J].
ALETTA, JM .
NEUROREPORT, 1994, 5 (16) :2090-2092
[2]   INCREASED EXPRESSION AND SUBCELLULAR TRANSLOCATION OF THE MITOGEN-ACTIVATED PROTEIN-KINASE KINASE AND MITOGEN-ACTIVATED PROTEIN-KINASE IN ALZHEIMERS-DISEASE [J].
ARENDT, T ;
HOLZER, M ;
GROSSMANN, A ;
ZEDLICK, D ;
BRUCKNER, MK .
NEUROSCIENCE, 1995, 68 (01) :5-18
[3]  
Arendt T, 2000, ANN NY ACAD SCI, V920, P249
[4]   NACP/α-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy [J].
Arima, K ;
Uéda, K ;
Sunohara, N ;
Arakawa, K ;
Hirai, S ;
Nakamura, M ;
Tonozuka-Uehara, H ;
Kawai, M .
ACTA NEUROPATHOLOGICA, 1998, 96 (05) :439-444
[5]  
Baba M, 1998, AM J PATHOL, V152, P879
[6]   Neural apoptosis [J].
Bredesen, DE .
ANNALS OF NEUROLOGY, 1995, 38 (06) :839-851
[7]   SYNUCLEIN PROTEINS AND ALZHEIMERS-DISEASE [J].
BROOKES, AJ ;
STCLAIR, D .
TRENDS IN NEUROSCIENCES, 1994, 17 (10) :404-405
[8]  
Busser J, 1998, J NEUROSCI, V18, P2801
[9]  
Cheng LA, 1999, MOL CELL BIOL, V19, P4270
[10]  
CLAUDIO PP, 1994, CANCER RES, V54, P5556