Cover image for Vol. 35 Issue 1

Edited By: Toru Iwaki

Impact Factor: 1.796

ISI Journal Citation Reports © Ranking: 2013: 46/76 (Pathology); 120/194 (Clinical Neurology); 190/252 (Neurosciences)

Online ISSN: 1440-1789

Virtual Issue: ALS - Discovery of TDP-43 & Subsequent Developments

This virtual issue is composed of an invited review series based on a symposium titled “AMYOTROPHIC LATERAL SCLEROSIS. DISCOVERY OF TDP-43 AND SUBSEQUENT DEVELOPMENT"

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Co-localization of Bunina bodies and TDP-43 inclusions in lower motor neurons in amyotrophic lateral sclerosis
Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron involvement with Bunina bodies (BBs) and transactivation response DNA protein 43 (TDP-43) inclusions. We examined the spinal cord (n = 20), hypoglossal nucleus (n = 6) and facial nucleus (n = 5) from ALS patients to elucidate the relationship between BBs and TDP-43 inclusions. Co-localization of BBs and TDP-43 inclusions was found in 15.2% of total neurons in the anterior horn, 29.2% in the hypoglossal nucleus and 17.3% in the facial nucleus. The frequency of TDP-43 inclusions was significantly higher in neurons with BBs than in those without in each region. Ultrastructurally, TDP-43-positive filamentous structures were intermingled with BBs. These findings suggest that there is a close relationship in the occurrence between BBs and TDP-43 inclusions.

TDP-43 pathology in polyglutamine diseases: With reference to amyotrphic lateral sclerosis
Yasuko Toyoshima, Hitoshi Takahashi

A nuclear protein, transactivation response (TAR) DNA binding protein 43 kDa (TDP-43), is the major component of neuronal cytoplasmic inclusions (NCIs) in frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). While initially thought to be relatively specific to FTLD-U and ALS, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Here, with a review of the literature, we discuss the relationship between ALS and polyQ diseases from the viewpoint of TDP-43 neuropathology.

Adenoviral expression of TDP-43 and FUS genes and shRNAs for protein degradation pathways in rodent motoneurons in vitro and in vivo
Kazuhiko Watabe, Keiko Akiyama, Emiko Kawakami, Tomohiro Ishii, Kentaro Endo, Hiroko Yanagisawa, Kazunori Sango, Masami Tsukamoto

Formation of cytoplasmic aggregates in neuronal and glial cells is one of the pathological hallmarks of amyotrophic lateral sclerosis (ALS). Mutations in two genes encoding transactivation response (TAR) DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), both of which are main constituents of cytoplasmic aggregates, have been identified in patients with familial and sporadic ALS. Impairment of protein degradation machineries has also been recognized to participate in motoneuron degeneration in ALS. The present study finds the co-infections of adenovirus encoding shRNA for PSMC1, ATG5 or VPS24 with TDP-43 or FUS adenovirus enhanced cytoplasmic aggregate formation in facial motoneurons, suggesting that impairment of protein degradation pathways accelerates formation of TDP-43 and FUS-positive aggregates in ALS.

Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases
Osamu Onodera, Tomohiko Ishihara, Atsushi Shiga, Yuko Ariizumi, Akio Yokoseki, Masatoyo Nishizawa

To explore the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-DNA binding protein 43 kDa (TDP-43) must be elucidated. TDP-43 is a nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which regulate the splicing of pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of pre-mRNA splicing. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.