title: TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor.
abstract: The aggregation and mislocalization of RNA-binding proteins leads to the aberrant regulation of RNA metabolism and is a key feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. However, the pathological consequences of abnormal deposition of TDP-43 and other RNA-binding proteins remain unclear, as the specific molecular events that drive neurodegeneration have been difficult to identify and continue to be elusive. Here, we provide novel insight into the complexity of the RNA-binding protein network by demonstrating that the inclusion of exon 17b in the SORT1 mRNA, a pathologically relevant splicing event known to be regulated by TDP-43, is also considerably affected by additional RNA-binding proteins, such as hnRNP L, PTB/nPTB and hnRNP A1/A2. Most importantly, the expression of hnRNP A1/A2 and PTB/nPTB is significantly altered in patients with frontotemporal dementia with TDP-43-positive inclusions (FTLD-TDP), indicating that perturbations in RNA metabolism and processing in FTLD-TDP are not exclusively driven by a loss of TDP-43 function. These results also suggest that a comprehensive assessment of the RNA-binding protein network will dramatically advance our current understanding of the role of TDP-43 in disease pathogenesis, as well as enhance both diagnostic and therapeutic capabilities.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy and.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Mohagheghi
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Prudencio
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy and.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Stuani
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Cook
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224, USA buratti@icgeb.org petrucelli.leonard@mayo.edu.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy and buratti@icgeb.org petrucelli.leonard@mayo.edu.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000235:genetics / Q000378:metabolism; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D000099183:Sortilin; C439788:C1 HNRNP; C000598624:TARDBP protein, human; C439768:hnRNP A2