Biochemistry, Biophysics, and Structural Biology Commons^™

Expression Of Fused In Sarcoma Mutations In Mice Recapitulates The Neuropathology Of Fus Proteinopathies And Provides Insight Into Disease Pathogenesis, Christophe Verbeeck, Mariely Dejesus-Hernandez, Carolina Ceballos-Diaz, Jannet Kocerha, Todd Golde, Pritam Das, Rosa Rademakers, Dennis W. Dickson, Thomas Kukar

Jannet Kocerha

Background: Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) can cause familial and sporadic amyotrophic lateral sclerosis (ALS) and rarely frontotemproal dementia (FTD). FUS accumulates in neuronal cytoplasmic inclusions (NCIs) in ALS patients with FUS mutations. FUS is also a major pathologic marker for a group of less common forms of frontotemporal lobar degeneration (FTLD), which includes atypical FTLD with ubiquitinated inclusions (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD). These diseases are now called FUS proteinopathies, because they share this disease marker. It is unknown how FUS mutations cause disease …

Altered Microrna Expression In Frontotemporal Lobar Degeneration With Tdp-43 Pathology Caused By Progranulin Mutations, Jannet Kocerha, Naomi Kouri, Matt Baker, Nicole Finch, Mariely Dejesus-Hernandez, John Gonzalez, Kumaravel Chidamparam, Keith A. Josephs, Bradley F. Boeve, Neill R. Graff-Radford, Julia Crook, Dennis W. Dickson, Rosa Rademakers

Jannet Kocerha

Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (PGRN) gene.

Results

Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.

Conclusions

Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and …