Expression of p25, an Aberrant Cyclin-Dependent Kinase 5 Activator, Stimulates Basal Secretion in PC12 Cells

다국어 초록 (Multilingual Abstract)

Although alterations in the functions of neurotransmitter systems have been implicated in the pathology of Alzheimer’s disease (AD), the mechanisms that give rise to these alterations are not well understood. The amount of p25, an aberrant cleavage product of p35 that activates cyclin-dependent kinase 5 (Cdk5), is elevated in AD brains.
The role of Cdk5 in neurotransmitter release has been well established. In this study, we examined whether p25 was linked to altered neurotransmitter release in AD. Transient or stable expression of p25 significantly increased basal secretion of human growth hormone (hGH) or neurotransmitter in PC12 cells. Expression of a p25 phosphorylation-deficient mutant, T138A, inhibited basal hGH secretion relative to the p25 wild type, suggesting the involvement of Thr138 phosphorylation in secretion. The expression and activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key protease in the generation of β-amyloid, are increased in AD brains. Our previous studies indicated that overexpression of BACE1 enhanced basal secretion of hGH in PC12 cells. Transient coexpression of p25 and BACE1 further stimulated spontaneous basal secretion. These results indicate a novel role for p25 in the secretory pathway and suggest that elevated levels of p25 and BACE1 in AD brains may contribute to altered neurotransmitter pathology of AD through enhancing spontaneous basal secretion.

참고문헌 (Reference)

1 Patrick, G.N., "p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway" 273 : 24057-24064, 1998

2 Cruz, J.C., "p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo" 26 : 10536-10541, 2006

3 Wen, Y., "Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing" 57 : 680-690, 2008

4 Chung, S.H., "The C2 domains of Rabphilin3A specifically bind phosphatidylinositol 4,5-bisphosphate containing vesicles in a Ca2+-dependent manner. In vitro characteristics and possible significance" 273 : 10240-10248, 1998

5 Sugita, S., "Synaptogyrins regulate Ca2+-dependent exocytosis in PC12 cells" 274 : 18893-18901, 1999

6 Kamei, H., "Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation" 282 : 1687-1694, 2007

7 van den Pol, A.N., "Selective neuronal expression of green fluorescent protein with cytomegalovirus promoter reveals entire neuronal arbor in transgenic mice" 18 : 10640-10651, 1998

8 Barclay, J.W., "Regulation of the fusion pore conductance during exocytosis by cyclin-dependent kinase 5" 279 : 41495-41503, 2004

9 Fletcher, A.I., "Regulation of exocytosis by cyclin- dependent kinase 5 via phosphorylation of Munc18" 274 : 4027-4035, 1999

10 Smith, C.C., "Putative amino acid transmitters in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia" 48 : 469-471, 1985

11 Lee, H.W., "Overexpression of BACE1 stimulates spontaneous basal secretion in PC12 cells" 421 : 178-183, 2007

12 Lee, H.W., "Overexpression of APP stimulates basal and constitutive exocytosis in PC12 cells" 436 : 245-249, 2008

13 Lanari, A., "Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer’s disease. Mech" 127 : 158-165, 2006

14 Jimenez-Jimenez, F.J., "Neurotransmitter amino acids in cerebrospinal fluid of patients with Alzheimer’s disease" 105 : 269-277, 1998

15 Swatton, J.E., "Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain" 19 : 2711-2719, 2004

16 Pomara, N., "Glutamate and other CSF amino acids in Alzheimer’s disease" 149 : 251-254, 1992

17 Rosales, J.L., "GTPdependent secretion from neutrophils is regulated by Cdk5" 279 : 53932-53936, 2004

18 Rosales, J.L., "Extraneuronal roles of cyclindependent kinase 5" 28 : 1023-1034, 2006

19 Palmada, M., "Excitatory amino acid neurotransmission. Pathways for metabolism, storage and reuptake of glutamate in brain" 3 : 701-718, 1998

20 Graham, M.E., "Evidence against an acute inhibitory role of nSec-1 (munc-18) in late steps of regulated exocytosis in chromaffin and PC12 cells" 69 : 2369-2377, 1997

21 Yang, L.B., "Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease" 9 : 3-4, 2003

22 Elrod, R., "Effects of Alzheimer's disease severity on cerebrospinal fluid norepinephrine concentration" 154 : 25-30, 1997

23 Khvotchev, M.V., "Divergent functions of neuronal Rab11b in Ca2+- regulated versus constitutive exocytosis" 23 : 10531-10539, 2003

24 Varro, A., "Discrimination between constitutive secretion and basal secretion from the regulated secretory pathway in GH3 cells" 1313 : 101-105, 1996

25 Saito, T., "Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation" 23 : 1189-1197, 2003

26 Chung, S.H., "Cyclin-dependent kinase 5: a critical regulator of neurotransmitter release. In cyclin dependent kinase 5 (Cdk5)" Springer US 35-50, 2008

27 Lilja, L., "Cyclin-dependent kinase 5 promotes insulin exocytosis" 276 : 34199-34205, 2001

28 Lilja, L., "Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis" 279 : 29534-29541, 2004

29 Patrick, G.N., "Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration" 402 : 615-622, 1999

30 Matsuuchi, L., "Constitutive and basal secretion from the endocrine cell line,AtT-20." 112 : 843-852, 1991

31 Chung, S.H., "Comparison of the effects on secretion in chromaffin and PC12 cells of Rab3 family members and mutants. Evidence that inhibitory effects are independent of direct interaction with Rabphilin3" 274 : 18113-18120, 1999

32 Tomizawa, K., "Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Qtype voltage-dependent calcium channel activity" 22 : 2590-2597, 2002

33 Young-Gil Jeong, "Cdk5/p35 Expression in the Mouse Ovary" 한국분자세포생물학회 17 (17): 17-22, 2004

34 Xin, X., "Cdk5 and Trio modulate endocrine cell exocytosis" 117 : 4739-4748, 2004

35 Csernansky, J.G., "CSF excitatory amino acids and severity of illness in Alzheimer’s disease" 46 : 1715-1720, 1996

36 Tandon, A., "Brain levels of CDK5 activator p25 are not increased in Alzheimer’s or other neurodegenerative diseases with neurofibrillary tangles" 86 : 572-581, 2003

37 Fukumoto, H., "Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease" 59 : 1381-1389, 2002

38 Soo Jung Choi, "Ameliorating Effect of Gardenia jasminoides Extract on Amyloid Beta Peptide-induced Neuronal Cell Deficit" 한국분자세포생물학회 24 (24): 113-118, 2007

39 Selkoe, D.J., "Alzheimer’s disease is a synaptic failure" 298 : 789-791, 2002

40 Fu, A.K., "Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclindependent kinase 5 null mice" 102 : 15224-15229, 2005

41 Cruz, J.C., "Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles" 40 : 471-483, 2003

42 Tseng, H.C., "A survey of Cdk5 activator p35 and p25 levels in Alzheimer’s disease brains" 523 : 58-62, 2002

43 Holz, R.W., "10. Synaptic transmission and cellular signaling: an overview in basic neurochemistry" Lippincott Williams & Wilkins 1999