Abstract
Ubiqitinated and TDP-43 immunoreactive cytoplasmic aggregates are hallmark features of ALS molecular pathology. Since clinically most ALS begins focally and advances contiguously, it is important to characterize their distribution. Our objective was to determine the extent and distribution of TDP-43 immunoreactive aggregates in the lower motor neuron columns as a function of disease onset, and to correlate ubiquitinated with TDP-43 aggregates in the lumbar region. We examined TDP-43 cytoplasmic aggregates at four separate neuraxis levels – hypoglossal nucleus and cervical, thoracic, and lumbar anterior horns – in five controls and 20 sporadic ALS nervous systems from patients whose disease began in various sites, i.e. five bulbar, five arm, five trunk, and five leg onsets. We correlated ubiquitinated to TDP-43 aggregates on adjacent histological sections for the lumbar regions. We found that TDP-43 cytoplasmic aggregates are seen in about 8% of motor neurons but there is marked variability between nervous systems, ranging from 0.4% to 20.6%. The aggregates are uniformly distributed within individual nervous systems. There is no obvious correlation between site of disease onset and rate of spread. Almost all ubiquitinated aggregates correlate to TDP-43 aggregates. Thus, TDP-43 immunoreactive cytoplasmic aggregates have a low overall average frequency that does not correlate with either disease course or clinical spread and is the prime ubiquitinated protein.
Highlights
In 1988, ubiquitinated cytoplasmic aggregates were identified as being distinctive of amyotrophic lateral sclerosis (ALS) neuropathology [1]
TAR DNA-binding protein 43 (TDP-43) immunoreactive cytoplasmic aggregates were seen in all 20 ALS nervous systems (Figure 1)
We found relatively low frequency and highly variable degrees of TDP-43 immunoreactive cytoplasmic aggregates over the rostral-caudal expanse of the lower motor neuron columns between different sporadic ALS (SALS) nervous systems, but fairly uniform distribution between neuraxis levels within individual nervous systems
Summary
In 1988, ubiquitinated cytoplasmic aggregates were identified as being distinctive of amyotrophic lateral sclerosis (ALS) neuropathology [1]. TDP-43 cytoplasmic aggregates have been clearly identified in sporadic ALS (SALS) and nonSOD1 familial ALS (FALS) [4,5]. Recent studies have indicated that TDP-43 abnormalities exist in a wide range of other neurodegenerative diseases including frontotemporal lobar dementia with ubiquitinated pathology, corticobasal degeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, and hippocampal sclerosis. Primary mutations in the TARDBP gene that encodes TDP-43 have been identified in 3% of FALS and 1–5% of SALS [6,7,8], indicating that disturbance of this protein itself may result in disease. Recent evidence suggests that the protein's toxicity may be related to soluble rather than aggregated insoluble protein [10,11]
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