ArticleNeurobiology of aging2011
Declining phosphatases underlie aging-related hyperphosphorylation of neurofilaments.
Article in Neurobiology of aging, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- Neurofilament Biophysics: From Structure to Biomechanics.Molecular biology of the cell · 2024Review
- Article
- Autophagosome-lysosome fusion is facilitated by plectin-stabilized actin and keratin 8 during macroautophagic process.Cellular and molecular life sciences : CMLS · 2022Article
- Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease.Frontiers in aging neuroscience · 2021Article
- MicroRNA profiles of MS gray matter lesions identify modulators of the synaptic protein synaptotagmin-7.Brain pathology (Zurich, Switzerland) · 2020Article
- Flexibility Is Costly: Hidden Physiological Damage From Seasonal Phenotypic Transitions in Heterothermic Species.Frontiers in physiology · 2020Article
- Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons.eLife · 2019Article
- Modulation of serine/threonine phosphatases by melatonin: therapeutic approaches in neurodegenerative diseases.British journal of pharmacology · 2018Review
- Neurofilaments and Neurofilament Proteins in Health and Disease.Cold Spring Harbor perspectives in biology · 2017Review
- Protein phosphatase modulation of somatostatin receptor signaling in the mouse hippocampus.Neuropharmacology · 2015Article
- Protein phosphatase 2A is involved in the tyrosine hydroxylase phosphorylation regulated by α-synuclein.Neurochemical research · 2015Article
- GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A.Autophagy · 2015Article
- The influence of aging on the number of neurons and levels of non-phosporylated neurofilament proteins in the central auditory system of rats.Frontiers in aging neuroscience · 2015Article
- Loss of prion protein leads to age-dependent behavioral abnormalities and changes in cytoskeletal protein expression.Molecular neurobiology · 2014Article
- Divergent and convergent roles for kinases and phosphatases in neurofilament dynamics.Journal of cell science · 2014Article
- A novel approach to rapidly prevent age-related cognitive decline.Aging cell · 2014Article
- Post-translational modifications of intermediate filament proteins: mechanisms and functions.Nature reviews. Molecular cell biology · 2014Review
- Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection.Acta neuropathologica · 2014Article
- Article
- PP2A ligand ITH12246 protects against memory impairment and focal cerebral ischemia in mice.ACS chemical neuroscience · 2013Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.