Abstract Details

Title Inhibition of MicroRNA-183 Attenuates Pathological TDP-43 Aggregation via SQSTM1/p62 in ALS

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S5 - ALS and CMT: New Therapeutic Approaches (4:42 PM-4:54 PM)

Poster/Presentation
Number 007

Background

Emerging evidence indicates that miRNA dysregulation is associated with neuronal toxicity and mitochondrial dysfunction, and also plays a pivotal role in ALS pathogenesis. MiR-183-5p was found to be elevated in serum exosomes from ALS patients. We recently reported that miR-183-5p is aberrantly upregulated in spinal cord tissues of ALS patients and promotes TDP-43 aggregation, mislocalization and neurotoxicity. Protein aggregation is a common pathological hallmark in neurodegenerative disease, and TDP-43 aggregation plays a key role in the pathogenesis of ALS. Preventing TDP-43 aggregation is therefore a rational approach for mitigating disease pathology.

Objective To define miR-183-5p as a viable target for TDP-43 aggregation and neurotoxicity, and to validate its therapeutic role in reversing TDP-43 pathology in ALS.

Design/Methods Real-time qPCR will be used to analyze miR-183-5p expression. ALS disease protein TDP-43 will be analyzed by western blot with miR-183-5p inhibitor transduced-neuronal cells. Soluble and insoluble fractions will be used to analyze the mitigation of TDP-43 aggregation. Immunostaining was used to visualize TIA1-positive SGs and subcellular location of mutant TDP-43.

Results MiR-183-5p increased TDP-43 expression, aggregation and stress-induced cytotoxicity. SQSTM1/p62 was suppressed by miR-183-5p via the 3’ untranslated region. Silencing SQSTM1/p62 recapitulates the increase in TDP-43 expression and aggregation as observed with miR-183-5p. Under heat shock and oxidative stress, we observed cytoplasmic association and stress granules of TDP43 and p62. The miR-183-5p antagomir repressed formation of stress granules and aggregated TDP43 protein in neuronal cells under stress-induced conditions and protected against cytotoxicity. These findings suggest that the miR-183-5p-SQSTM1/p62 axis plays a key role in the pathophysiology of ALS by promoting TDP-43 aggregation and cellular toxicity.

Conclusions Our discovery of miR-183-5p as a novel regulator of TDP-43 aggregation via p62 highlights the convergence of abnormal RNA processing and protein recycling in ALS pathogenesis, providing a therapeutic target to rescue TDP-43 pathology in ALS.

Authors/Disclosures
Liang Lu, MD, FAAN (MEDVAMC/BCM) PRESENTER	Dr. Lu has nothing to disclose.
Han-Cheon Kim	No disclosure on file
Yan Zhang	No disclosure on file
Peter H. King, MD	The institution of Dr. King has received research support from Department of Veterans Affairs. The institution of Dr. King has received research support from NIH.