Summary
In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemann-Pick disease type C (NPC) (npc−/−), recombinant adeno-associated virus (rAAV) carrying the small interfering RNA (siRNA) specific for cdk-5 gene was injected into 3-day-old npc−/− mice intracerebroventricularly. The rAAV-GFP-injected age-matched npc−/− mice and non-surgery age-matched npc−/− mice were employed as controls (n=6−10/group). From the 4th to 8th week after the treatment, mice were weighed, and evaluated for limb motor activity by using the coat hanger test once a week. Eight-week-old npc−/− mice were sacrificed by decapitation, and brains were quickly dissected and halved sagittally. Immunohistochemistry, Western blotting, and HE staining were used to evaluate the neuropathology in npc−/− mice. The results showed that rAAV-cdk-5-siRNA-GFP significantly reduced the number of axonal spheroids, delayed the death of Purkinje neurons, ameliorated motor defects in npc−/− mice, and significantly attenuated the hyperphosphorylation of tau proteins. These data suggested that inhibition of cdk-5 activity has neuroprotective effect on neurons in NPC mice.
Similar content being viewed by others
References
Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci, 2001,24:1121–1159
Delisle MB, Carpenter S. Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J Neurol Sci, 1984,63:241–250
Axelsson R, Roytta M, Sourander P, et al. Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand, 1984,69(Suppl 314):1–65
Zhou L, Miller BL, McDaniel CH, et al. Frontotemporal dementia: neuropil spheroids and presynaptic terminal degeneration. Ann Neurol, 1998,44:99–109
Bu B, Klunemann H, Suzuki K, et al. Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles. Neurobiol Dis, 2002,11:285–297
Zhang M, Li J, Chakrabarty P, et al. Cyclin-dependent kinase inhibitors attenuate protein hyperphos-phorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick type C mice. Am J Pathol, 2004,165:843–853
Loftus SK, Morris JA, Carstea ED, et al. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science, 1997,277:232–235
Hallows JL, Chen K, DePinho RA, et al. Decreased cyclindependent kinase 5 (cdk5) activity is accompanied by redistribution of cdk5 and cytoskeletal proteins and increased cytoskeletal protein phosphorylation in p35 null mice. J Neurosci, 2003,23:10633–10644
Voikar V, Rauvala H, Ikonen E. Cognitive deficit and development of motor impairment in a mouse model of Niemann-Pick type C disease. Behav Brain Res, 2002,132:1–10
Herrup K, Arendt T. Re-expression of cell cycle proteins induces neuronal cell death during Alzheimer’s disease. J Alzheimers Dis, 2002,4:243–247
Elleder M, Jirasek A. Neuropathology of various types of Niemann-Pick disease. Acta Neuropathol Suppl (Berl), 1981,7:201–203
Lisa D, Griffin, WH Gong, et al. Niemann-Pick type C disease involves disrupted neurosteroidgenesis and responds to allopregnanolone. Nat Med, 2004,10:704–711
Matsushita M, Tomizawa K, YF Lu, et al. Distinct cellular compartment of cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activator protein (p35nck5a) in the developing rat cerebellum. Brain Res, 1996,734:1–2
Janice L. Hallows JL, Robert E, et al. p35/p25 is not essential for tau and cytoskeletal pathology or neuronal loss in niemann-pick type C disease. J Neurosci, 2006,26:2738–2744
Bitao Bu, Jin Li, Davies P, et al. Deregulation of cdk5, hyperphosphorylation, and cytoskeletalPathology in the Niemann-Pick type C murine model. J Neurosci, 2002, 22:6515–6525
Vincent I, Jicha G, Rosado M, et al. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci, 1997,17: 3588–3598
Busser J, Geldmacher DS, Herrup K. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci, 1998,18: 2801–2807
Nguyen MD, Boudreau M, Kriz J, et al. Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci, 2003, 23:2131–2140
Camins A, Verdaguer E, Folch J, et al. The role of CDK5/P25 formation/inhibition in neurodegeneration. Drug News Perspect, 2006,19:453
Author information
Authors and Affiliations
Additional information
Youguo HAO and Dengji PAN contributed equally to this study.
This study was supported by a grant from the National Natural Sciences Foundation of China (No. 30400141, 30670737).
Rights and permissions
About this article
Cite this article
Hao, Y., Pan, D., Zhang, M. et al. The neuroprotective effects of cyclin-dependent kinase-5 inhibition in mice with Niemann-Pick disease type C. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 29, 324–329 (2009). https://doi.org/10.1007/s11596-009-0312-0
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-009-0312-0