title: TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP-43 has been identified as a component of ubiquitin-immunoreactive inclusions of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP-43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP-43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP-43 immunoreactivity was higher than that of ubiquitin-immunoreactive ones. The percentage of TDP-43-positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP-43, the immunoblot analysis of spinal cord and frontal cortex showed that full-length TDP-43, the 45 kDa form and ubiquitinated TDP-43 are found in the soluble inclusion-free fraction. The present data suggest that delocalization, accumulation and ubiquitination of TDP-43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.
authors.affiliation: Department of Neuroscience, Section of Biochemistry, University of Turin, Turin, Italy. mariateresa.giordana@unito.it
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Giordana
authors.forename: Marco
authors.initials: M
authors.lastname: Piccinini
authors.forename: Silvia
authors.initials: S
authors.lastname: Grifoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Marco
authors.forename: Marco
authors.initials: M
authors.lastname: Vercellino
authors.forename: Michela
authors.initials: M
authors.lastname: Magistrello
authors.forename: Alessia
authors.initials: A
authors.lastname: Pellerino
authors.forename: Barbara
authors.initials: B
authors.lastname: Buccinnà
authors.forename: Elisa
authors.initials: E
authors.lastname: Lupino
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Rinaudo