UC San Diego

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are overlapping neurodegenerative diseases characterized by dysfunction of RNA binding proteins (RBPs). The hallmark of greater than 95% of ALS and nearly half of FTLD cases involve the RBP TDP-43 (FTLD-TDP43), which mislocalizes from the nucleus and forms hyperphosphorylated cytoplasmic aggregations. In FTLD related to hyperphosphorylated tau aggregates (FTLD-Tau), RBP dysfunction is also present. Our group has identified ELAVL3 as an RBP dysregulated in ALS spinal cord. Like TDP-43, ELAVL3 is involved in mRNA stability, alternative splicing and polyadenylation, and transcription rate. Low transcript levels of ELAVL3 and mislocalization of ELAVL3 protein out of the nuclear compartment is characteristic of ALS spinal cord motor neurons. ELAVL3 has been identified as a target gene of TDP-43. Loss of TDP-43 nuclear splice function results in expression of non-conserved exonic sequences (cryptic exons, CEs). These inserted sequences can induce frameshifting, add premature stop or polyadenylation sequences, and/or changes the protein coding sequence. ELAVL3 shows expression of CE 4a with in vitro knockdown of TDP-43 and FTLD-TDP43 frontal cortex. Here, we report evidence for a pathogenic link between ELAVL3 and TDP-43 or Tau aggregates in ALS/FTLD brain and spinal cord. We confirm the expression of ELAVL3 CE 4a in 40-70% of ALS spinal cord and motor cortex using multiple modalities. We predict ELAVL3 downregulation seen in anterior horn motor neurons is due to production of CE 4a-containing transcripts destined for destruction via non-sense mediated decay. We also expand previous neuropathologic findings of ELAVL3 nuclear loss in ALS spinal cord motor neurons. We demonstrate ALS Betz cells are resilient to pathologic changes to ELAVL3 expression relative to spinal cord motor neurons; however, neurons of layers 3 and 5 of the motor cortex have reduced nuclear ELAVL3 expression. We show a triad of ELAVL3 pathologic findings in ALS motor cortex and FTLD frontal cortex: (1) reduction of nuclear ELAVL3 expression in the presence of intracellular phosphorylated tau (pTau) or phosphorylated TDP-43 (pTDP-43), (2) rare cortical cells with ELAVL3 nuclear depletion and granular cytoplasmic aggregation, and (3) neuropil ELAVL3 “beads on a string” aggregates.