title: Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.
abstract: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine. P.le Santa Maria della Misericordia 15, 33100, Udine, Italy. dardis.andrea@aoud.sanita.fvg.it.
authors.forename: A
authors.initials: A
authors.lastname: Dardis
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine. P.le Santa Maria della Misericordia 15, 33100, Udine, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zampieri
authors.affiliation: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Università "La Sapienza", Roma, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Canterini
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Kansas School of Medicine, Kansas City, Kansas.
authors.forename: K L
authors.initials: KL
authors.lastname: Newell
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Area Science Park, 34194, Trieste, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Stuani
authors.affiliation: Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: J R
authors.initials: JR
authors.lastname: Murrell
authors.affiliation: Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Università "La Sapienza", Roma, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Fiorenza
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine. P.le Santa Maria della Misericordia 15, 33100, Udine, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Bembi
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Area Science Park, 34194, Trieste, Italy. buratti@icgeb.org.
authors.forename: E
authors.initials: E
authors.lastname: Buratti
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D000111:Acetylcysteine; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D000077296:Niemann-Pick C1 Protein; D011506:Proteins; D047392:beta-Cyclodextrins; C106831:Npc1 protein, mouse; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse; C031215:betadex
keywords: Lysosomal diseases; NPC1; Niemann Pick C; TDP-43