Activation of the Akt1-CREB pathway promotes RNF146 expression to inhibit PARP1-mediated neuronal death.

ABSTRACT

Progressive degeneration of dopaminergic neurons characterizes Parkinson's disease (PD). This neuronal loss occurs through diverse mechanisms, including a form of programmed cell death dependent on poly(ADP-ribose) polymerase-1 (PARP1) called parthanatos. Deficient activity of the kinase Akt1 and aggregation of the protein α-synuclein are also implicated in disease pathogenesis. Here, we found that Akt1 suppressed parthanatos in dopaminergic neurons through a transcriptional mechanism. Overexpressing constitutively active Akt1 in SH-SY5Y cells or culturing cells with chlorogenic acid (a polyphenol found in coffee that activates Akt1) stimulated the CREB-dependent transcriptional activation of the gene encoding the E3 ubiquitin ligase RNF146. RNF146 inhibited PARP1 not through its E3 ligase function but rather by binding to and sequestering PAR, which enhanced the survival of cultured cells exposed to the dopaminergic neuronal toxin 6-OHDA or α-synuclein aggregation. In mice, intraperitoneal administration of chlorogenic acid activated the Akt1-CREB-RNF146 pathway in the brain and provided neuroprotection against both 6-OHDA and combinatorial α-synucleinopathy in an RNF146-dependent manner. Furthermore, dysregulation of the Akt1-CREB pathway was observed in postmortem brain samples from patients with PD. The findings suggest that therapeutic restoration of RNF146 expression, such as by activating the Akt1-CREB pathway, might halt neurodegeneration in PD.