title: Alterations in subcellular localization of TDP-43 immunoreactivity in the anterior horns in sporadic amyotrophic lateral sclerosis.
abstract: TDP-43 is ubiquitously expressed in the nucleus of motor neurons and is closely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). However, little is known about alterations in the subcellular or intracellular localization of TDP-43, either under normal conditions or in ALS. We examined the anterior horn neurons of the spinal cord in patients with sporadic ALS and age-matched controls immunohistochemically and immunoelectron-microscopically using anti-TDP-43 antibody. Immunohistochemically, the present study showed a decrease in TDP-43 immmunoreactivity in the nucleus and, by contrast, an increase in the cytoplasm in ALS patients. Immunoelectron-microscopically, we demonstrated the consistent presence of TDP-43-immunogold-labeled deposits primarily in the nucleus, particularly in the nucleolus, and frequently in the rough endoplasmic reticulum (rER), and, to a lesser extent, in the mitochondria and the synaptic vesicles of the presynaptic terminals on the surface of anterior horn neurons both in controls and ALS subjects. In ALS, a reduced number of TDP-43-immunogold-labeled deposits were observed in the nuclei, particularly in the nucleoli of even normal-looking motor neurons. In contrast, the number of TDP-43-immunogold-labeled deposits in the rER of the normal-appearing motor neurons was significantly larger in ALS than in the controls (p=0.0036). These findings suggest that TDP-43 is synthesized in the rER and translocates to the nucleus, particularly to the nucleolus, and in ALS, TDP-43 trafficking between the nucleus and the cytoplasm is disturbed, resulting in an accumulation of TDP-43 in the cytoplasm in the form of insoluble aggregates.
authors.affiliation: Department of Neurology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. ssasaki@nij.twmu.ac.jp
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shibata
authors.forename: Makio
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000870:Anterior Horn Cells / Q000378:metabolism* / Q000648:ultrastructure; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism; D006801:Humans; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins