Accumulation of p62 in degenerated spinal cord under chronic mechanical compression

Abstract

Intracellular accumulation of altered proteins, including p62 and ubiquitinated proteins, is the basis of most neurodegenerative disorders. The relationship among the accumulation of altered proteins, autophagy, and spinal cord dysfunction by cervical spondylotic myelopathy has not been clarified. We examined the expression of p62 and autophagy markers in the chronically compressed spinal cord of tiptoe-walking Yoshimura mice. In addition, we examined the expression and roles of p62 and autophagy in hypoxic neuronal cells. Western blot analysis showed the accumulation of p62, ubiquitinated proteins, and microtubule-associated protein 1 light chain 3 (LC3), an autophagic marker, in the compressed spinal cord. Immunohistochemical examinations showed that p62 accumulated in neurons, axons, astrocytes, and oligodendrocytes. Electron microscopy showed the expression of autophagy markers, including autolysosomes and autophagic vesicles, in the compressed spinal cord. These findings suggest the presence of p62 and autophagy in the degenerated compressed spinal cord. Hypoxic stress increased the expression of p62, ubiquitinated proteins, and LC3-II in neuronal cells. In addition, LC3 turnover assay and GFP-LC3 cleavage assay showed that hypoxic stress increased autophagy flux in neuronal cells. These findings suggest that hypoxic stress induces accumulation of p62 and autophagy in neuronal cells. The forced expression of p62 decreased the number of neuronal cells under hypoxic stress. These findings suggest that p62 accumulation under hypoxic stress promotes neuronal cell death. Treatment with 3-methyladenine, an autophagy inhibitor decreased the number of neuronal cells, whereas lithium chloride, an autophagy inducer increased the number of cells under hypoxic stress. These findings suggest that autophagy promotes neuronal cell survival under hypoxic stress. Our findings suggest that pharmacological inducers of autophagy may be useful for treating cervical spondylotic myelopathy patients.

Contribution of p62 to Phenotype Transition of Coronary Arterial Myocytes with Defective Autophagy

“…Through LIR motif and UBA domain, p62 interacts with ATG8 family and ubiquitinated proteins which is essential for the formation of autophagosomes and degradation of proteins [8]. However, excessive p62 is harmful as shown by the findings that p62 accumulation was associated with neurodegeneration [12, 13], cancer cell proliferation and migration [11] or podocytes epithelial-to-mesenchymal transition [31]. Similarly, in the present work, by using genetic and pharmacological manipulations, we found that p62 accumulation induced by CD38 gene deficiency or lysosomal dysfunction was a major contributor to the proliferation and dedifferentiation change of CAMs.…”

“…The p62 mediated selective autophagic clearance of proteins provides an important degradation mechanism, especially when organisms are under the influence of mutation, aging, or environmental stresses [9]. A defect in autophagy may result in an p62 accumulation associated with a host of detrimental effects including rapid tumor growth with adverse prognostic behavior [10], distant metastases [11], neuropathology [12], and neurodegenerative disorders [13]. In the present study, we sought to elucidate whether the p62 accumulation elicited the proliferation and phenotype change of CAMs following autophagy defect induced by CD38 gene deficiency or lysosomal disorder.…”

The effect of spinal osteotomies on spinal cord tension and dural buckling: a cadaveric study

“…3B and F). The rates of tension reduction were 24.9%/mm (r 2 = 0.939) for the mean 20-g baseline, 25.0%/mm (r 2 = 0.959) for the mean 40-g baseline, and 24.9%/mm (r 2 = 0.953) for the mean of the 2 trials within this span.…”

“…While tension previously has been investigated in human cadaveric models of tethered cord syndrome, 8 dural buckling has only been investigated in animal models. 1,16,19,25 We hypothesized that 2 parameters define the boundaries of this region: tension reduction and dural buckling. The primary aim of this study was to better define the range of tension reduction and dural buckling in a human cadaveric model.…”

Intrathecal Injection of 3-Methyladenine Reduces Neuronal Damage and Promotes Functional Recovery <i>via</i> Autophagy Attenuation after Spinal Cord Ischemia/Reperfusion Injury in Rats

“…[2][3][4] In recent years, evidence has indicated that autophagy may play an important role in various spinal disease models, including spinal cord contusion injury, spinal cord hemisection injury, and cervical spondylotic myelopathy. [5][6][7] However, the occurrence and role of autophagy in neural tissues following spinal cord I/R injury have not been clearly illustrated.…”