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: Chun-Feng Tan, Mitsunori Yamada, Yasuko Toyoshima, Akio Yokoseki, Yukari Miki, Yasuhiro Hoshi, Hiroyuki Kaneko, Takeshi Ikeuchi, Osamu Onodera, Akiyoshi Kakita, Hitoshi Takahashi
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 118 Issue 4 Pg. 553-60 (Oct 2009) ISSN: 1432-0533 [Electronic] Germany
• PMID: 19526244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Blotting, Western
• Brain (metabolism, pathology)
• Cell Death
• DNA-Binding Proteins (metabolism)
• Female
• Fluorescent Antibody Technique
• Humans
• Immunohistochemistry
• Inclusion Bodies (metabolism, pathology)
• Machado-Joseph Disease (metabolism, pathology)
• Male
• Microscopy, Immunoelectron
• Middle Aged
• Motor Neurons (metabolism, pathology)
• Muscular Atrophy, Spinal (metabolism, pathology)
• Spinal Cord (metabolism, pathology)