Abstract Details

Title Pathologic Changes in ELAVL3 Expression and Splicing Occur in TDP43 and Non-TDP43 Proteinopathies

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P4 - Poster Session 4 (11:45 AM-12:45 PM)

Poster/Presentation
Number 9-007

Background ALS and FLTD are a heterogenous spectrum neurodegenerative diseases involving dysfunction of RBPs, mostly commonly TDP-43. Loss of TDP-43 function results in pathologic splicing changes in target genes including Stmn2 and Unc13a. The RBP Elavl3 is also target gene of TDP-43. We have previously demonstrated that ELAVL3 is downregulated and mislocalized from the nucleus of ALS spinal cord motor neurons independent of TDP-43 pathology. In vitro TDP-43 loss induces expression of a cryptic exon between exons 3 and 4.

Objective

To describe the neuropathologic and splicing changes in the RNA binding protein (RBP) ELAVL3 in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

Design/Methods We evaluated expression of protein ELAVL3 using immunofluorescent intensity in post-mortem motor cortex (controls and ALS) and frontal cortex (controls, FTLD-TDP43, and FTLD-Tau). We analyzed expression of Elavl3, including changes in splicing, using RT-qPCR and in situ hybridization.

Results

expression is reduced in motor cortex neurons of ALS and frontal cortex neurons of FTLD-TDP-43 and FTLD-Tau compared to control throughout the cortical layers. Presence of an intracellular TDP-43 or tau aggregate was unlinked from ELAVL3 nuclear mislocalization. Elavl3 mRNA was expressed lower in ALS compared to control in both spinal cord and motor cortex. Expression of cryptic exon 4a is also detected more commonly in ALS compared to control.

Conclusions

We showed the RBP ELAVL3 shows significant neuropathologic changes with or without TDP-43 pathology. We also confirmed the expression of cryptic exon 4a within human tissue. We hypothesize that expression ELAVL3 can be significantly downregulated by TDP-43 loss, in part due to expression of cryptic exon 4a causing nonsense-mediated decay. However, ELAVL3 downregulation and nuclear mislocalization is not a unique feature of TDP-43opathies but instead represents a common target of multiple protein aggregate pathologies.

Authors/Disclosures
Isabel Costantino, PhD (U of California San Diego) PRESENTER	Ms. Costantino has nothing to disclose.
Isabel Costantino, PhD (U of California San Diego)	Ms. Costantino has nothing to disclose.
John M. Ravits, MD, FAAN (University of California, San Diego)	Dr. Ravits has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Iris, Inc. Dr. Ravits has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Maze, Inc. Dr. Ravits has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Transposon, Inc. Dr. Ravits has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Libra, Inc. The institution of Dr. Ravits has received research support from NIH R21 Research Grant. The institution of Dr. Ravits has received research support from NIH R01 Research Grant. The institution of Dr. Ravits has received research support from FightMND Foundation Research Grant. The institution of Dr. Ravits has received research support from DOD Research Grant. Dr. Ravits has received personal compensation in the range of $0-$499 for serving as a Reviewer with NIH Office of Scientific Review.