Therapeutic Potentials of Poly (ADP-Ribose) Polymerase 1 (PARP1) Inhibition in Multiple Sclerosis and Animal Models:...

Poly (ADP-ribose) polymerase 1 (PARP1) plays a fundamental role in DNA repair and gene expression. Excessive PARP1 hyperactivation, however, has been associated with cell death. PARP1 and/or its activity are dysregulated in the immune and central nervous system of multiple sclerosis (MS) patients and animal models. Pharmacological PARP1 inhibition is shown to be protective against immune activation and disease severity in MS animal models while genetic PARP1 deficiency studies reported discrepant results. The inconsistency suggests that the function of PARP1 and PARP1-mediated PARylation may be complex and context-dependent. The article reviews PARP1 functions, discusses experimental findings and possible interpretations of PARP1 in inflammation, neuronal/axonal degeneration, and oligodendrogliopathy, three major pathological components cooperatively determining MS disease course and neurological progression, and points out future research directions. Cell type specific PARP1 manipulations are necessary for revisiting the role of PARP1 in the three pathological components prior to moving PARP1 inhibition into clinical trials for MS therapy.