title: Declining phosphatases underlie aging-related hyperphosphorylation of neurofilaments.
abstract: Cytoskeletal protein phosphorylation is frequently altered in neuropathologic states but little is known about changes during normal aging. Here we report that declining protein phosphatase activity, rather than activation of kinases, underlies aging-related neurofilament hyperphosphorylation. Purified PP2A or PP2B dephosphorylated the heavy neurofilament (NFH) subunit or its extensively phorphorylated carboxyl-terminal domain in vitro. In cultured primary hippocampal neurons, inhibiting either phosphatase induced NFH phosphorylation without activating known neurofilament kinases. Neurofilament phosphorylation in the mouse CNS, as reflected by levels of the RT-97 phosphoepitope associated with late axon maturation, more than doubled during the 12-month period after NFH expression plateaued at p21. This was accompanied by declines in levels and activity of PP2A but not PP2B, and no rise in activities of neurofilament kinases (Erk1,2, cdk5 and JNK1,2). Inhibiting PP2A in mice in vivo restored brain RT-97 to levels seen in young mice. Declining PP2A activity, therefore, can account for rising neurofilament phosphorylation in maturing brain, potentially compounding similar changes associated with adult-onset neurodegenerative diseases.
authors.affiliation: Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, United States; Department of Psychiatry, New York University School of Medicine, New York, NY 10016, United States.
authors.lastname: Veeranna
authors.forename: Dun-Sheng
authors.initials: DS
authors.lastname: Yang
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: K Yaragudri
authors.initials: KY
authors.lastname: Vinod
authors.forename: Philip
authors.initials: P
authors.lastname: Stavrides
authors.forename: Niranjana D
authors.initials: ND
authors.lastname: Amin
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
chemical_list: D051360:Cyclin-Dependent Kinase 5; D010744:Phosphoric Monoester Hydrolases