title: The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies.
abstract: Retinoblastoma protein (pRb) is a ubiquitous 928-amino acid cell cycle regulatory molecule with diverse biologic activities. One critical function 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 of cell 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 cell cycle 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 (3 cases 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 cycle progression in neurodegenerative diseases, particularly tauopathies, and suggest a novel target for therapeutic intervention.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Stone
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
authors.forename: Asao
authors.initials: A
authors.lastname: Hirano
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.forename: Corrado
authors.initials: C
authors.lastname: Santocanale
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Hyoung-gon
authors.initials: HG
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000145:classification / Q000473:pathology*; D055815:Young Adult; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C054369:MAPT protein, human; D016160:Retinoblastoma Protein; D016875:tau Proteins