Neurotropic Alphaviruses activate PARP-1 Dependent Cell Death Mechanisms in Infected Motor Neurons 9207

Abstract Description Alphaviruses are arthropod-borne viruses that are known to cause neurological sequalae following infection, including encephalomyelitis, headaches, ataxia, seizures, paralysis, cognitive impairment, and neurodegeneration. Several alphaviruses, including Venezuelan equine encephalitis virus (VEEV) and Chikungunya virus (CHIKV) are capable of directly infecting cortical, hippocampal, and motor neurons. We have previously shown that infected cortical and hippocampal neurons primarily die in an apoptotic manner. However, the primary cell death mechanism that motor neurons undergo during infection isn’t well characterized. Activation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is a key signal for certain caspase-independent cell death mechanisms, including parthanatos and necrosis. Using human induced pluripotent stem cell (hIPSC) derived motor neurons, we first showed that CHIKV and VEEV infections lead to activation of PARP-1. This is followed by translocation of poly(ADP-ribose) (PAR) and apoptosis-inducing factor (AIF), key signals in parthanatos. Inhibition or degradation of PARP-1 in motor neurons leads to significantly increased cell survival and viability during infection. These results indicate that PARP-1 dependent cell death mechanisms may be activated during alphavirus infections of motor neurons. As motor neuron cell death plays a key role in paralysis, these findings may help us to better understand disease progression and treatment options. Topic Categories Neuroimmunology (NEUR)