Parkinson’s Disease (PD) is the second most frequent, degenerative neurological condition affecting up to ten million worldwide and occurs through loss of dopamine-producing neurons. PD etiology/pathogenesis remain incompletely understood, however, mitochondrial dysfunction, protein aggregation and neuroinflammation play a role in PD development. FK506 binding proteins (FKBP) belong to the highly conserved immunophilin superfamily of proteins with fundamental roles in protein folding/receptor signaling/protein trafficking/molecular chaperone activity. Several members of the FKBP family are promising therapeutic targets including in neurodegeneration.

Robson/Annett have extensively characterized a divergent member of this family, FK506 binding like protein (FKBPL), in cancer/inflammatory disease via regulation of angiogenesis, stem cell differentiation, and NF-kappa-β-associated inflammation. Here we aim to explore a new therapeutic indication for this protein in PD as new FKBPL biology has arisen. FKBPL binds to and induces degradation of dual leucine zipper kinase (DLK). DLK is highly expressed in the nervous system and, of note, DLK strongly regulates neurodegeneration in PD by JNK activation. We therefore predict that FKBPL-based therapeutics could induce DLK degradation, inhibiting JNK, leading to neuroprotection; in addition to FKBPL’s anti-neuroinflammatory action, inhibiting innate immune signalling induced by alpha-synuclein aggregates.