title: Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization.
abstract: Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337Vmice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43M337Vmice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43M337Vmice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43M337Vmice. Thus, this study suggests hemizygous TDP-43M337Vmice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Rodent Behavioral Core, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Luwen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Ogoegbunam
authors.initials: O
authors.lastname: Okolo
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Yinfei
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Petersen
authors.affiliation: Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA. Electronic address: xinglong.wang@case.edu.
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D008124:Locomotion; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D009043:Motor Activity; D053580:Muscle Strength; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments; D021381:Protein Transport; D011597:Psychomotor Performance
chemical_list: D004268:DNA-Binding Proteins; D010446:Peptide Fragments; C578077:Tardbp protein, mouse
keywords: ALS; FTD; TDP-43; cognitive deficit; mitochondrial dysfunction; motor dysfunction; neurodegeneration; transgenic mice