TY - JOUR
T1 - The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies
AU - Stone, Jeremy G.
AU - Siedlak, Sandra L.
AU - Tabaton, Massimo
AU - Hirano, Asao
AU - Castellani, Rudy J.
AU - Santocanale, Corrado
AU - Perry, George
AU - Smith, Mark A.
AU - Zhu, Xiongwei
AU - Lee, Hyoung Gon
PY - 2011/7
Y1 - 2011/7
N2 - Retinoblastoma protein (pRb) is a ubiquitous 928-amino acid cell cycle regulatory molecule with diverse biologic activities. One criticalfunction of pRb is the control of the G1-to-S phase checkpoint of the cell cycle. In the hypophosphorylated state, pRb suppresses the activity of E2F transcription factors thereby inhibiting transcription ofcell cycle-promoting genes. On phosphorylation, primarily by cyclin-dependent kinases, phosphorylated pRb dissociates from E2F and permits cell cycle progression. We previously found phosphorylated pRb to be intimately associated with hyperphosphorylated tau-containing neurofibrillary tangles of Alzheimer disease (AD), the pathogenesis of which is believed to involve dysregulation of the cellcycle and marked neuronal death. Here, we used immunohistochemistry to investigate the presence of phosphorylated pRb in other distinct neurodegenerative diseases that share the common characteristic of hyperphosphorylated tau pathology and neuronal loss with AD.We found colocalized labeling of tau pathology and phosphorylated pRb in Pick disease and progressive supranuclear palsy (3cases each), neurodegeneration with brain iron accumulation type 1 (2 cases), and Parkinson-amyotrophic lateral sclerosis of Guam, subacute sclerosing panencephalitis, frontotemporal dementia and Parkinsonism linked to chromosome 17, and dementia pugilistica (1 case each). These observations further implicate aberrant neuronal cell cycleprogression in neurodegenerative diseases, particularly tauopathies, and suggest a novel target for therapeutic intervention.
AB - Retinoblastoma protein (pRb) is a ubiquitous 928-amino acid cell cycle regulatory molecule with diverse biologic activities. One criticalfunction of pRb is the control of the G1-to-S phase checkpoint of the cell cycle. In the hypophosphorylated state, pRb suppresses the activity of E2F transcription factors thereby inhibiting transcription ofcell cycle-promoting genes. On phosphorylation, primarily by cyclin-dependent kinases, phosphorylated pRb dissociates from E2F and permits cell cycle progression. We previously found phosphorylated pRb to be intimately associated with hyperphosphorylated tau-containing neurofibrillary tangles of Alzheimer disease (AD), the pathogenesis of which is believed to involve dysregulation of the cellcycle and marked neuronal death. Here, we used immunohistochemistry to investigate the presence of phosphorylated pRb in other distinct neurodegenerative diseases that share the common characteristic of hyperphosphorylated tau pathology and neuronal loss with AD.We found colocalized labeling of tau pathology and phosphorylated pRb in Pick disease and progressive supranuclear palsy (3cases each), neurodegeneration with brain iron accumulation type 1 (2 cases), and Parkinson-amyotrophic lateral sclerosis of Guam, subacute sclerosing panencephalitis, frontotemporal dementia and Parkinsonism linked to chromosome 17, and dementia pugilistica (1 case each). These observations further implicate aberrant neuronal cell cycleprogression in neurodegenerative diseases, particularly tauopathies, and suggest a novel target for therapeutic intervention.
KW - Dementia pugilistica
KW - Neurodegeneration with brain iron accumulation type 1
KW - Neurofibrillary tangles
KW - Pick disease
KW - Progressive supranuclear palsy
KW - Retinoblastoma protein
KW - Subacute sclerosing panencephalitis
KW - Tau pathology
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U2 - 10.1097/NEN.0b013e3182204414
DO - 10.1097/NEN.0b013e3182204414
M3 - Article
C2 - 21666500
AN - SCOPUS:79959512528
SN - 0022-3069
VL - 70
SP - 578
EP - 587
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 7
ER -