Early upregulation of cytosolic phospholipase A(2)α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A(2) alpha (cPLA(2)α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA(2)α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1(G93A)) was detected long before the development of the disease, and inhibition of cPLA(2)α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA(2)α upregulation. METHODS: Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA(2)α 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 cPLA(2)α upregulation. Elevated expression of both misfolded SOD1 and cPLA(2)α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1(G93A) mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA(2)α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA(2)α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA(2)α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA(2)α upregulation in a dose dependent manner. CONCLUSIONS: Motor neurons expressing elevated cPLA(2)α and TNFα 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 cPLA(2)α upregulation via induction of TNFα. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02326-5.