Encephalitic Alphavirus Infection Induces PARP-1 Hyperactivation Mediated Energy Collapse in Motor Neurons

Area of Science:

• Neuroscience
• Virology
• Molecular Biology

Background:

• Motor neurons are susceptible to metabolic stress.
• Neurotropic alphavirus infections, like VEEV, cause motor neuron injury through unclear mechanisms.
• Caspase-independent cell death pathways are implicated in alphavirus-infected motor neurons.

Purpose of the Study:

• To elucidate the intrinsic pathways of motor neuron degeneration during VEEV infection.
• To investigate the role of poly(ADP-ribose) polymerase-1 (PARP-1) in VEEV-induced motor neuron death.
• To determine if targeting PARP-1 can mitigate neuronal injury.

Main Methods:

• VEEV infection of murine NSC34 motor neuron-like cells and human iPSC-derived motor neurons.
• Assessment of PARP-1 activation, NAD+/ATP levels, and mitochondrial membrane potential.
• Pharmacological inhibition and genetic reduction of PARP-1.
• Evaluation of cell survival rates.

Main Results:

• VEEV infection led to sustained PARP-1 activation.
• PARP-1 hyperactivation resulted in NAD+ and ATP depletion, preceding cell death.
• Inhibition or reduction of PARP-1 partially restored cellular energy levels and improved motor neuron survival.
• PARP-1 was identified as a key contributor to energy failure and motor neuron death.

Conclusions:

• PARP-1 hyperactivation is a critical mechanism driving energy collapse and motor neuron death during VEEV infection.
• Targeting PARP-1 represents a potential therapeutic strategy to limit neuronal injury in neurotropic viral infections.