title: Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons.
abstract: Under normal conditions, the proline-directed serine/threonine residues of neurofilament tail-domain repeats are exclusively phosphorylated in axons. In pathological conditions such as amyotrophic lateral sclerosis (ALS), motor neurons contain abnormal perikaryal accumulations of phosphorylated neurofilament proteins. The precise mechanisms for this compartment-specific phosphorylation of neurofilaments are not completely understood. Although localization of kinases and phosphatases is certainly implicated, another possibility involves Pin1 modulation of phosphorylation of the proline-directed serine/threonine residues. Pin1, a prolyl isomerase, selectively binds to phosphorylated proline-directed serine/threonine residues in target proteins and isomerizes cis isomers to more stable trans configurations. In this study we show that Pin1 associates with phosphorylated neurofilament-H (p-NF-H) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration, we studied glutamate-stressed neurons that displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin1 and led to cell death. Both effects were reduced upon inhibition of Pin1 activity by the use of an inhibitor juglone and down-regulating Pin1 levels through the use of Pin1 small interfering RNA. Thus, isomerization of lys-ser-pro repeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation, which suggests that Pin1 inhibition may be an attractive therapeutic target to reduce pathological accumulations of p-NF-H.
authors.affiliation: Cytoskeletal Protein Regulation Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Zheng
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.forename: Mia
authors.initials: M
authors.lastname: Bjelogrlic
authors.forename: Wayne
authors.initials: W
authors.lastname: Albers
authors.forename: Niranjana
authors.initials: N
authors.lastname: Amin
authors.forename: Howard
authors.initials: H
authors.lastname: Jaffe
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.forename: Philip
authors.initials: P
authors.lastname: Grant
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000201:enzymology; D005799:Genes, Dominant; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D008954:Models, Biological; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D016900:Neurofilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014162:Transfection
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D016900:Neurofilament Proteins; D034741:RNA, Small Interfering; C051774:neurofilament protein H; D018698:Glutamic Acid; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C005134:juglone