The role of miRNA biogenesis and decay in spinal muscular atrophy

• Applicant: Professorin Dr. Brunhilde Wirth, since 4/2020
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269018619

In neurons, subcellular compartments contain different sets of proteins and their expressions are spatially segregated and transient. To explain this phenomenon, it has been suggested that proteins can be locally synthesized and degraded at subcellular compartments such as dendrites and axonal terminals. This can explain neuron specific phenomena such as axonal pathfinding and synaptic plasticity, which require spatial and temporal regulation of protein expression. Several different mechanisms regulating specific protein synthesis have been suggested in neurons, including microRNA (miRNA) mediated translational repression. Therefore, deciphering miRNA expression and distribution in neuron will help us to understand neuronal gene expression system. Importantly, multiple lines of evidence over the past decade have indicated critical roles for local protein homeostasis in association with neurological disorders as diverse as spinal muscular atrophy (SMA) and autism spectrum disorders. SMA is a devastating inherited neuromuscular disorder, which causes dysfunction/loss of motor neurons and muscle weakness. The majority of SMA is caused by lower amount of SMN (Survival motor neuron) protein expression, which is due to deletion or mutation in SMN1 gene (Survival of motor neuron 1). SMN plays an important role for RNA mediated gene expression such as splicesome formation, pre-mRNA processing as well as RNA trafficking. However, cellular pathomechanisms explaining SMA phenotype caused by SMN deficiency is not yet fully understood. This hinders to develop efficient therapy for SMA patients and currently there is no cure available for SMA. Recently, we found that expression and distribution of miRNAs are dysregulated in SMA neurons and counteracting dysregulated miRNA expression significantly improved SMA phenotype in mouse model. In this proposal, we suggest to further characterize the pathomechanism of miRNA dysregulation/distribution in SMA neurons as well as basic cellular process underlying neuronal miRNA distribution and expression. We found that expression of Xrn1 and Xrn2, which are important for miRNA decay, is down regulated in spinal cord of SMA mice. In addition, expression of Drosha, which plays a role for miRNA biogenesis is also dysregulated in spinal cords of SMA mice. Therefore, we will investigate the cellular mechanism of miRNA biogenesis and decay in neurons as well as their contribution to SMA pathology. The proposed research will significantly contribute to the basic understanding of neuronal miRNA expression and distribution, which is important for neuronal development and function. In addition, this will identify new pathological mechanism of spinal muscular atrophy.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Min Jeong Kye, Ph.D., until 3/2020