title: The C-terminal TDP-43 fragments have a high aggregation propensity and harm neurons by a dominant-negative mechanism.
abstract: TAR DNA binding protein 43 KD (TDP-43) is an essential gene that regulates gene transcription, mRNA splicing and stability. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal neurodegenerative diseases, TDP-43 is fragmented, generating multiple fragments that include the C-terminal fragment of ∼25 KD. The role of these fragments in the pathogenesis of ALS and FTD is not clear. Here we investigated the aggregation propensity in various polypeptide regions of TDP-43 in mammalian cells and the effect of these fragments on cultured neurons. By expressing the full length and various TDP-43 fragments in motor neuron-derived NSC-34 cells and primary neurons, we found that both N- and C-terminal fragments of TDP-43 are prone to aggregate and the C-terminal end of RRM2 region is required, though not sufficient, for aggregation. The aggregation of the TDP-43 fragments can drive co-aggregation with the full-length TDP-43, consequently reducing the nuclear TDP-43. In addition, the TDP-43 fragments can impair neurite growth during neuronal differentiation. Importantly, overexpression of the full-length TDP-43 rescues the neurite growth phenotype whereas knockdown of the endogenous TDP-43 reproduces this phenotype. These results suggest that TDP-43 fragments, particularly the pathologically relevant C-terminal fragments, can impair neuronal differentiation by dominant-negatively interfering with the function of the full length TDP-43, thus playing a role in pathogenesis in ALS and FTD.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Chunxing
authors.initials: C
authors.lastname: Yang
authors.forename: Weijia
authors.initials: W
authors.lastname: Tan
authors.forename: Catheryne
authors.initials: C
authors.lastname: Whittle
authors.forename: Linghua
authors.initials: L
authors.lastname: Qiu
authors.forename: Lucheng
authors.initials: L
authors.lastname: Cao
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.forename: Zuoshang
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000737:chemistry*; D005091:Exons; D005799:Genes, Dominant; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins