A Translational Investigation of Discoidin Domain Receptor 1 Inhibition as a Novel Therapeutics Strategy in Neurodegenerative Disease

Abstract

Neurodegenerative diseases (ND) are gaining recognition as imminent health crises. The greatest unmet need in neurodegeneration is a disease modifying therapy, but the failures of drug development have not been for a lack of trying. Protein aggregation is a well described feature of neurodegenerative diseases and is the focus of most experimental therapies, although incompletely understood. Previous work from Dr. Moussa’s lab has established impairments in autophagy and upregulation of several tyrosine kinases (TK) as additional features. Here, I combined pharmacological and genetic tools to evaluate the Discoidin Domain Receptor 1 (DDR1) receptor TK as a putative therapeutic target in NDs and link the three aforementioned features. I found that LCB, an experimental DDR inhibitor, lowers α-synuclein (α-syn) and protects dopaminergic cells in the midbrains of lentiviral α-syn mice. We next developed BK40143, a novel small molecule. I demonstrated that BK40143 could cross the blood brain barrier (BBB) in mice, specifically inhibit DDR1, and reduce phosphorylated tau, amyloid-β, and α-syn in mice expressing human mutant P301L tau (Tg4510), human mutant SwDI APP, and human mutant A53T α-syn, respectively. When our LVsyn inducible mouse model was combined with a DDR1 knockout (DDR1KO) mouse line, we observed no added effect of BK40143, and that loss of DDR1, one or both alleles, reduces also α-syn levels. A recent study demonstrated that oral nilotinib in PD reaches sufficient cerebrospinal fluid (CSF) concentrations to inhibit DDR1. Therefore, we investigated the effects of DDR1 inhibition on gene regulation by evaluating longitudinal microRNAs (miRNAs) expression. CSF miRNAs expression patterns reveal early autophagic and vascular impairments in moderately severe PD over 12 months, which correlate with declines in motor and non-motor outcomes. Conversely, in 300mg nilotinib treated PD patients, miRNAs expression patterns reveal successful completion of autophagy through the lysosome, maintenance of the BBB, and modulation of neuroinflammatory responses. These data suggest DDR1 may have multiple roles in neurodegeneration depending on the cell type, microenvironment, and ND context. DDR1 inhibition is a promising therapeutic option for ND and these data warrant further investigation of its role in ND.