Short TDP-43 Isoforms as Therapeutic Targets and Biomarkers for Amyotrophic Lateral Sclerosis
Abstract
Even though the majority of amyotrophic lateral sclerosis (ALS) patients have no family history of the disease or defined genetic risk factor, almost all exhibit nuclear clearance and cytoplasmic accumulation of transactive response DNA binding protein 43 (TDP-43), an RNA-binding protein critical for RNA processing. However, the mechanisms responsible forTDP-43 mislocalization and their impact on neuronal survival remain elusive. We recently uncovered two uncommon splicing events predicted to generate TDP-43 isoforms carrying a cryptic nuclear export sequence in an 18 amino acid segment replacing the canonical C-terminus. The cytoplasmic distribution of these highly insoluble shortened (s)TDP-43 isoforms is upregulated by hyperactivity another unexplained phenomenon in ALS and downregulated by silencing neuronal activity. Importantly, these sTDP-43 isoforms retain the ability to interact with full-length (fl)TDP-43, and consequently recruit it to cytoplasmic aggregates. event neurodegeneration in ALS. Moreover, we expect specific knockdown of shortened TAR DNA-binding protein(sTARDBP)
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2023
- Accession Number
- AD1205949
Entities
People
- Paul Valdmanis
- Sami Barmada
- Veronique Belzil
Organizations
- Mayo Clinic