title: Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado-Joseph disease.
abstract: Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado-Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at ~23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, 1-757 Asahimachi, Niigata, Japan.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Tan
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Yamada
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.forename: Yukari
authors.initials: Y
authors.lastname: Miki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hoshi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D017827:Machado-Joseph Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins