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 ubiquitinimmunoreactive 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.

Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

“…This redistribution of TDP-43 to the cytoplasm has been suggested to represent a landmark feature of the onset and progression of ALS/FTLD [23, 43], and in cell culture the disrupted trafficking of TDP-43 is a precursor to the formation of cytoplasmic TDP-43 inclusions [66]. Previously, Sato et al, [54] have reported the cytoplasmic mislocalisation of TDP-43 in response to neuronal stress in a mouse ligation model.…”

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

“…The mechanisms by which mutations in TARDBP cause neurodegeneration are unclear. Pathological assembly is associated with a marked reduction in nuclear TDP-43 staining and the cytoplasmic accumulation of TDP-43 is believed to be an early event (Giordana et al 2010). A combination of loss of function and gain of toxic function mechanisms may be at play.…”

ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS

“…In disease conditions, affected neurons typically lose nuclear TDP-43 staining, possibly before the formation of intracellular aggregates (21). In addition, TDP-43 seems to be ubiquitinylated, phosphorylated, and fragmented in pathological conditions (3).…”