2024 American Academy of Neurology Abstract Website

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).

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.

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.