Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons.
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.
Kesavapany
Sashi
S
Cytoskeletal Protein Regulation Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Patel
Vyomesh
V
Zheng
Ya-Li
YL
Pareek
Tej K
TK
Bjelogrlic
Mia
M
Albers
Wayne
W
Amin
Niranjana
N
Jaffe
Howard
H
Gutkind
J Silvio
JS
Strong
Michael J
MJ
Grant
Philip
P
Pant
Harish C
HC
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
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