Enhanced p62 expression triggers concomitant autophagy and apoptosis in a rat chronic spinal cord compression model

Chen,Zhi; Fu,Qingge; Shen,Baoliang; Huang,Xuan; Wang,Kun; He,Ping; Li,Fengning; Zhang,Fan; Shen,Hongxing

doi:10.3892/mmr.2014.2124

Enhanced p62 expression triggers concomitant autophagy and apoptosis in a rat chronic spinal cord compression model

Authors:
- Zhi Chen
- Qingge Fu
- Baoliang Shen
- Xuan Huang
- Kun Wang
- Ping He
- Fengning Li
- Fan Zhang
- Hongxing Shen
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Affiliations: Department of Orthopaedics, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, P.R. China, Department of Emergency and Trauma, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, Department of Orthopaedics, Shanghai Jiading Central Hospital, Shanghai 201800, P.R. China
Published online on: April 8, 2014 https://doi.org/10.3892/mmr.2014.2124
Pages: 2091-2096

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Abstract

Chronic spinal cord compression is the result of mechanical pressure on the spinal cord, which in contrast to traumatic spinal cord injury, leads to slowly progressing nerve degeneration. These two types of spinal cord injuries may trigger similar mechanisms, including motoric nerve cell apoptosis and autophagy, however, depending on differences in the underlying injury severity, nerve reactions may predominantly involve the conservation of function or the initiation of functions for the removal of irreversibly damaged cells. p62 is a multidomain adapter protein, which is involved in apoptosis and cell survival as well as autophagy, and is a common component of protein aggregations in neurodegenerative diseases. In the present study, a rat chronic spinal cord compression model was used, in which the spinal cord was progressively compressed for six weeks and then constantly compressed for another 10 weeks. As a result Basso, Beattie and Bresnahan locomotor scaling revealed a gradual score decrease until the 6th week followed by constant recovery until the 16th week after spinal cord compression was initiated. During the first eight weeks of the experiment, p62 and nuclear factor‑κB (NF‑κB) were increasingly expressed up to a constant plateau at 12‑16 weeks, whereas caspase 3 exhibited a marginally enhanced expression at 8 weeks, however, reached a constant maximum peak 12‑16 weeks after the beginning of spinal cord compression. It was hypothesized that, in the initial phase of spinal cord compression, enhanced p62 expression triggered NF‑κB activity, directing the cell responses mainly to cell survival and autophagy, whereas following eight weeks of spinal cord compression, caspase 3 was additionally activated indicating cumulative elimination of irreversibly damaged nerve cells with highly activated autophagy.

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1	Hayashi H, Okada K, Hamada M, Tada K and Ueno R: Etiologic factors of myelopathy. A radiographic evaluation of the aging changes in the cervical spine. Clin Orthop Relat Res. 200–209. 1987.PubMed/NCBI
2	Ogino H, Tada K, Okada K, et al: Canal diameter, anteroposterior compression ratio, and spondylotic myelopathy of the cervical spine. Spine (Phila Pa 1976). 8:1–15. 1983. View Article : Google Scholar : PubMed/NCBI
3	Edwards WC and LaRocca H: The developmental segmental sagittal diameter of the cervical spinal canal in patients with cervical spondylosis. Spine (Phila Pa 1976). 8:20–27. 1983. View Article : Google Scholar : PubMed/NCBI
4	Ito T, Oyanagi K, Takahashi H, Takahashi HE and Ikuta F: Cervical spondylotic myelopathy. Clinicopathologic study on the progression pattern and thin myelinated fibers of the lesions of seven patients examined during complete autopsy. Spine (Phila Pa 1976). 21:827–833. 1996. View Article : Google Scholar
5	Gooding MR, Wilson CB and Hoff JT: Experimental cervical myelopathy. Effects of ischemia and compression of the canine cervical spinal cord. J Neurosurg. 43:9–17. 1975. View Article : Google Scholar : PubMed/NCBI
6	Hukuda S and Wilson CB: Experimental cervical myelopathy: effects of compression and ischemia on the canine cervical cord. J Neurosurg. 37:631–652. 1972. View Article : Google Scholar : PubMed/NCBI
7	Long HQ, Li GS, Hu Y, Wen CY and Xie WH: HIF-1alpha/VEGF signaling pathway may play a dual role in secondary pathogenesis of cervical myelopathy. Med Hypotheses. 79:82–84. 2012. View Article : Google Scholar : PubMed/NCBI
8	Fehlings MG and Skaf G: A review of the pathophysiology of cervical spondylotic myelopathy with insights for potential novel mechanisms drawn from traumatic spinal cord injury. Spine (Phila Pa 1976). 23:2730–2737. 1998. View Article : Google Scholar : PubMed/NCBI
9	Yu WR, Baptiste DC, Liu T, Odrobina E, Stanisz GJ and Fehlings MG: Molecular mechanisms of spinal cord dysfunction and cell death in the spinal hyperostotic mouse: implications for the pathophysiology of human cervical spondylotic myelopathy. Neurobiol Dis. 33:149–163. 2009. View Article : Google Scholar : PubMed/NCBI
10	Yu WR, Liu T, Kiehl TR and Fehlings MG: Human neuropathological and animal model evidence supporting a role for Fas-mediated apoptosis and inflammation in cervical spondylotic myelopathy. Brain. 134:1277–1292. 2011. View Article : Google Scholar : PubMed/NCBI
11	Kim DH, Vaccaro AR, Henderson FC and Benzel EC: Molecular biology of cervical myelopathy and spinal cord injury: role of oligodendrocyte apoptosis. Spine J. 3:510–519. 2003. View Article : Google Scholar : PubMed/NCBI
12	Karadimas SK, Gialeli CH, Klironomos G, et al: The role of oligodendrocytes in the molecular pathobiology and potential molecular treatment of cervical spondylotic myelopathy. Curr Med Chem. 17:1048–1058. 2010. View Article : Google Scholar : PubMed/NCBI
13	Hara T, Nakamura K, Matsui M, et al: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 441:885–889. 2006. View Article : Google Scholar : PubMed/NCBI
14	Komatsu M, Waguri S, Chiba T, et al: Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 441:880–884. 2006. View Article : Google Scholar : PubMed/NCBI
15	Sarkar S, Ravikumar B, Floto RA and Rubinsztein DC: Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 16:46–56. 2009. View Article : Google Scholar : PubMed/NCBI
16	Pan T, Kondo S, Zhu W, Xie W, Jankovic J and Le W: Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis. 32:16–25. 2008. View Article : Google Scholar : PubMed/NCBI
17	Wong E and Cuervo AM: Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 13:805–811. 2010. View Article : Google Scholar : PubMed/NCBI
18	Keane RW, Kraydieh S, Lotocki G, et al: Apoptotic and anti-apoptotic mechanisms following spinal cord injury. J Neuropathol Exp Neurol. 60:422–429. 2001.PubMed/NCBI
19	Yoshino O, Matsuno H, Nakamura H, et al: The role of Fas-mediated apoptosis after traumatic spinal cord injury. Spine (Phila Pa 1976). 29:1394–1404. 2004. View Article : Google Scholar : PubMed/NCBI
20	Casha S, Yu WR and Fehlings MG: FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury. Exp Neurol. 196:390–400. 2005. View Article : Google Scholar
21	Erlich S, Alexandrovich A, Shohami E and Pinkas-Kramarski R: Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol Dis. 26:86–93. 2007. View Article : Google Scholar : PubMed/NCBI
22	Sekiguchi A, Kanno H, Ozawa H, Yamaya S and Itoi E: Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J Neurotrauma. 29:946–956. 2012. View Article : Google Scholar : PubMed/NCBI
23	Duran A, Serrano M, Leitges M, et al: The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell. 6:303–309. 2004. View Article : Google Scholar : PubMed/NCBI
24	Rodriguez A, Durán A, Selloum M, et al: Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metab. 3:211–222. 2006. View Article : Google Scholar : PubMed/NCBI
25	Duran A, Linares JF, Galvez AS, et al: The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 13:343–354. 2008. View Article : Google Scholar
26	Kuusisto E, Salminen A and Alafuzoff I: Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport. 12:2085–2090. 2001. View Article : Google Scholar : PubMed/NCBI
27	Zatloukal K, Stumptner C, Fuchsbichler A, et al: p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol. 160:255–263. 2002. View Article : Google Scholar : PubMed/NCBI
28	Nagaoka U, Kim K, Jana NR, et al: Increased expression of p62 in expanded polyglutamine-expressing cells and its association with polyglutamine inclusions. J Neurochem. 91:57–68. 2004. View Article : Google Scholar : PubMed/NCBI
29	Komatsu M, Waguri S, Koike M, et al: Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 131:1149–1163. 2007. View Article : Google Scholar : PubMed/NCBI
30	Jin Z, Li Y, Pitti R, et al: Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell. 137:721–735. 2009. View Article : Google Scholar : PubMed/NCBI
31	Sanz L, Diaz-Meco MT, Nakano H and Moscat J: The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J. 19:1576–1586. 2000. View Article : Google Scholar : PubMed/NCBI
32	Moscat J, Diaz-Meco MT, Albert A and Campuzano S: Cell signaling and function organized by PB1 domain interactions. Mol Cell. 23:631–640. 2006. View Article : Google Scholar : PubMed/NCBI
33	Moscat J and Diaz-Meco MT: p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 137:1001–1004. 2009. View Article : Google Scholar : PubMed/NCBI
34	Xu P, Gong WM, Li Y, et al: Destructive pathological changes in the rat spinal cord due to chronic mechanical compression. Laboratory investigation. J Neurosurg Spine. 8:279–285. 2008. View Article : Google Scholar
35	Basso DM, Beattie MS and Bresnahan JC: A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 12:1–21. 1995. View Article : Google Scholar : PubMed/NCBI
36	Kuusisto E, Kauppinen T and Alafuzoff I: Use of p62/SQSTM1 antibodies for neuropathological diagnosis. Neuropathol Appl Neurobiol. 34:169–180. 2008. View Article : Google Scholar : PubMed/NCBI
37	Karin M and Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol. 3:221–227. 2002. View Article : Google Scholar : PubMed/NCBI
38	Sheikh MS and Huang Y: Death receptor activation complexes: it takes two to activate TNF receptor 1. Cell Cycle. 2:550–552. 2003. View Article : Google Scholar : PubMed/NCBI