Abstract
TDP-43 pathology in spinal motor neurons is a neuropathological hallmark of sporadic amyotrophic lateral sclerosis (ALS) and has recently been shown to be closely associated with the downregulation of an RNA editing enzyme called adenosine deaminase acting on RNA 2 (ADAR2) in the motor neurons of sporadic ALS patients. Because TDP-43 pathology is found more frequently in the brains of elderly patients, we investigated the age-related changes in the TDP-43 localization and ADAR2 activity in mouse motor neurons. We found that ADAR2 was developmentally upregulated, and its mRNA expression level was progressively decreased in the spinal cords of aged mice. Motor neurons normally exhibit nuclear ADAR2 and TDP-43 immunoreactivity, whereas fast fatigable motor neurons in aged mice demonstrated a loss of ADAR2 and abnormal TDP-43 localization. Importantly, these motor neurons expressed significant amounts of the Q/R site-unedited AMPA receptor subunit 2 (GluA2) mRNA. Because expression of unedited GluA2 has been demonstrated as a lethality-causing molecular abnormality observed in the motor neurons, these results suggest that age-related decreases in ADAR2 activity play a mechanistic role in aging and serve as one of risk factors for ALS.
Highlights
Given that abnormal processing and mislocalization of the 43kDa TAR DNA-binding protein (TDP-43) occurs in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) [1,2], much effort has been made to understand the molecular bases of the abnormalities that occur in TDP-43 proteinopathies
Despite the widespread reduction in the adenosine deaminase acting on RNA 2 (ADAR2) mRNA expression level in the aged mouse spinal cord, the age-dependent reduction in ADAR2 activity reached at a level insufficient to edit the Q/R site of all of the GluA2 mRNA only in the motor neurons in the lateral AHs of the elderly mice. We demonstrated that both TDP-43 and ADAR2 localized normally to the nuclei of the motor neurons of young and adult mice
TDP-43 mislocalized from the nucleus to the cytoplasm in association with a reduction of ADAR2 immunoreactivity in the nuclei of motor neurons in an age-dependent manner
Summary
Given that abnormal processing and mislocalization of the 43kDa TAR DNA-binding protein (TDP-43) occurs in a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) [1,2], much effort has been made to understand the molecular bases of the abnormalities that occur in TDP-43 proteinopathies. Recent studies on the spinal cords of patients with sporadic ALS have demonstrated that TDP-43 pathology exclusively appears in motor neurons with reduced expression of the RNA editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2) [3]. The ADAR2lacking motor neurons underwent slow cell death because of their failure to edit the Q/R site of GluA2, as observed in the conditional ADAR2 knockout (ADAR2flox/flox/VAChTCre.Fast, or AR2) mice [7]. This indicates that failure of the GluA2 Q/R site resulting from reduced ADAR2 expression is involved in the pathogenesis of sporadic ALS. Because the AMPA receptors that contain the Q/R site-unedited GluA2 are permeable to Ca2+, the neurotoxicity mediated by Ca2+-permeable AMPA receptors containing unedited GluA2 is likely the mechanism involved in the degeneration of motor neurons in sporadic ALS patients [8,9]
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