Inhibition of <i>miR-181a</i> promotes midbrain neuronal growth through a Smad1/5-dependent mechanism: implications for Parkinson’s disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, and is characterized by the progressive degeneration of nigrostriatal dopaminergic (DA) neurons. Current PD treatments are symptomatic, wear off over time and do not protect against DA neuronal loss. Finding a way to re-grow midbrain DA (mDA) neurons is a promising disease-modifying therapeutic strategy for PD. However, reliable biomarkers are required to allow such growth-promoting approaches to be applied early in the disease progression. <i>miR-181a</i> has been shown to be dysregulated in PD patients, and has been identified as a potential biomarker for PD. Despite studies demonstrating the enrichment of <i>miR-181a</i> in the brain, specifically in neurites of postmitotic neurons, the role of <i>miR-181a</i> in mDA neurons remains unknown. Herein, we used cell culture models of human mDA neurons to investigate a potential role for <i>miR-181a</i> in mDA neurons. We used a bioninformatics analysis to identify that <i>miR-181a</i> targets components of the bone morphogenetic protein (BMP) signalling pathway, including the transcription factors Smad1 and Smad5, which we find are expressed by rat mDA neurons and are required for BMP-induced neurite growth. We also found that inhibition of neuronal <i>miR-181a</i>, resulted in increased Smad signalling, and induced neurite growth in SH-SY5Y cells. Finally, using embryonic rat cultures, we demonstrated that <i>miR-181a</i> inhibition induces ventral midbrain (VM) and cortical neuronal growth. These data describe a new role for <i>miR-181a</i> in mDA neurons, and provide proof of principle that <i>miR-181a</i> dysresgulation in PD may alter the activation state of signalling pathways important for neuronal growth in neurons affected in PD.