Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies.
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.
Lee
S S
SS
Genetic Pharmacology Unit, Experimental Therapeutics Branch, NINDS, National Institutes of Health, 10 Center Drive, MSC 1406, Bethesda, MD 20892-1406, USA.
Kim
Y M
YM
Junn
E
E
Lee
G
G
Park
K-H
KH
Tanaka
M
M
Ronchetti
R D
RD
Quezado
M M
MM
Mouradian
M M
MM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002999:Clone Cells / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019926:Cyclin B / Q000378:metabolism*; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D005434:Flow Cytometry / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D051843:Synucleins; D013997:Time Factors; D014162:Transfection / Q000379:methods; D051844:alpha-Synuclein
D000900:Anti-Bacterial Agents; C534696:CCND3 protein, human; C534698:Ccnd3 protein, rat; D016895:Culture Media, Serum-Free; D019926:Cyclin B; D056743:Cyclin D3; D016213:Cyclins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D004247:DNA; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine; D004318:Doxycycline