Evaluation of ABT-888 in the amelioration of α-synuclein fibril-induced neurodegeneration

Lyndsay Hastings; Arpine Sokratian; Daniel J Apicco; Christina M Stanhope; Lindsey Smith; Warren D Hirst; Andrew B West; Kaela Kelly

doi:10.1093/braincomms/fcac042

Evaluation of ABT-888 in the amelioration of α-synuclein fibril-induced neurodegeneration

Brain Commun. 2022 Feb 22;4(2):fcac042. doi: 10.1093/braincomms/fcac042. eCollection 2022.

Authors

Lyndsay Hastings¹, Arpine Sokratian¹, Daniel J Apicco², Christina M Stanhope¹, Lindsey Smith³, Warren D Hirst⁴, Andrew B West¹, Kaela Kelly¹

Affiliations

¹ Duke Center for Neurodegeneration Research, Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
² Biogen Postdoctoral Scientist Program, Biogen, Cambridge, MA, USA.
³ Aiforia Inc., Cambridge, MA, USA.
⁴ Biogen Neurodegeneration Research Unit, Research and Early Discovery, Biogen, Cambridge, MA, USA.

Abstract

The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson's disease. Recent pre-clinical studies suggest poly(ADP-ribose) polymerase-1 activation and the subsequent generation of poly(ADP-ribose) polymer represent key steps in the formation of toxic α-synuclein aggregates and neurodegeneration. Several studies suggest that the inhibition of poly(ADP-ribose) polymerase-1 activity via the poly(ADP-ribose) polymerase-1/2 small molecule inhibitor ABT-888 (Veliparib), a drug in clinical trials for different cancers, may prevent or ameliorate α-synuclein fibril-induced aggregation, inclusion formation and dopaminergic neurodegeneration. Herein, we evaluated the effects of poly(ADP-ribose) polymer on α-synuclein fibrillization in vitro, the effects of ABT-888 on the formation of fibril-seeded α-synuclein inclusions in primary mouse cortical neurons and the effects of an in-diet ABT-888 dosage regimen with the intracranial injection of α-synuclein fibrils into the mouse dorsal striatum. We found that poly(ADP-ribose) polymer minimally but significantly increased the rate of spontaneously formed α-synuclein fibrils in vitro. Machine-learning algorithms that quantitatively assessed α-synuclein inclusion counts in neurons, both in primary cultures and in the brains of fibril-injected mice, did not reveal differences between ABT-888- and vehicle-treated groups. The in-diet administered ABT-888 molecule demonstrated outstanding brain penetration in mice; however, dopaminergic cell loss in the substantia nigra caused by α-synuclein fibril injections in the striatum was similar between ABT-888- and vehicle-treated groups. α-Synuclein fibril-induced loss of dopaminergic fibres in the dorsal striatum was also similar between ABT-888- and vehicle-treated groups. We conclude that additional pre-clinical evaluation of ABT-888 may be warranted to justify further exploration of ABT-888 for disease modification in Lewy body diseases.

Keywords: Parkinson’s disease; neurodegeneration; poly(ADP-ribose) polymerase-1; veliparib; α-synuclein.

Grants and funding

R01 NS064934/NS/NINDS NIH HHS/United States