| First Author | Malada Edelstein YF | Year | 2021 |
| Journal | J Neuroinflammation | Volume | 18 |
| Issue | 1 | Pages | 274 |
| PubMed ID | 34823547 | Mgi Jnum | J:315161 |
| Mgi Id | MGI:6830708 | Doi | 10.1186/s12974-021-02326-5 |
| Citation | Malada Edelstein YF, et al. (2021) Early upregulation of cytosolic phospholipase A2alpha in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 18(1):274 |
| abstractText | BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2alpha) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2alpha upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1(G93A)) was detected long before the development of the disease, and inhibition of cPLA2alpha upregulation delayed the disease's onset. The aim of the present study was to determine the mechanism for cPLA2alpha upregulation. METHODS: Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2alpha and inflammatory markers were performed in the spinal cord sections of SOD1(G93A) transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. RESULTS: Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1(G93A) mice before cPLA2alpha upregulation. Elevated expression of both misfolded SOD1 and cPLA2alpha was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFalpha levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1(G93A) mice. Elevated TNFalpha was specifically detected in the motor neurons and its expression was highly correlated with cPLA2alpha expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2alpha and TNFalpha upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2alpha upregulation which was prevented by antibodies against TNFalpha. The addition of TNFalpha to NSC34 cells caused cPLA2alpha upregulation in a dose dependent manner. CONCLUSIONS: Motor neurons expressing elevated cPLA2alpha and TNFalpha are in an inflammatory state as early as at 6 weeks old mutant SOD1(G93A) mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2alpha upregulation via induction of TNFalpha. |
