Yue Yang1, Glenda M Halliday1, Matthew C Kiernan1, Rachel H Tan2. 1. From the University of Sydney (Y.Y., G.M.H., M.C.K., R.H.T.), Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health; School of Medical Sciences (G.M.H., R.H.T.), University of New South Wales; Neuroscience Research Australia (G.M.H., R.H.T.); and Department of Neurology (M.C.K.), Royal Prince Alfred Hospital, Sydney, Australia. 2. From the University of Sydney (Y.Y., G.M.H., M.C.K., R.H.T.), Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health; School of Medical Sciences (G.M.H., R.H.T.), University of New South Wales; Neuroscience Research Australia (G.M.H., R.H.T.); and Department of Neurology (M.C.K.), Royal Prince Alfred Hospital, Sydney, Australia. rachel.tan1@sydney.edu.au.
Abstract
OBJECTIVE: To assess the amount of phosphorylated and nonphosphorylated TAR DNA-binding protein 43 (TDP-43) in the motor brain regions of cases of amyotrophic lateral sclerosis (ALS) with and without repeat expansions in the ATXN2 or C9ORF72 genes. METHODS: The 45-kDa phosphorylated form of TDP-43 and 43-kDa nonphosphorylated form of TDP-43 were quantified by immunoblot in postmortem brain tissue from the motor cortex, spinal cord, and cerebellar vermis of 23 cases with ALS with repeat expansions in the ATXN2 or C9ORF72 genes and sporadic disease and 10 controls. RESULTS: Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with C9ORF72 expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate ATXN2 expansions. In contrast, however, similar levels of nonphosphorylated TDP-43 were found in all 3 regions between ALS groups. CONCLUSION: Despite its central role in the pathogenesis of ALS and the emergence of potential targets to modify its aggregation, TDP-43 levels have not been quantified in pathologically confirmed cases with ALS. The present results demonstrating significant differences in phosphorylated but not nonphosphorylated TDP-43 levels suggest that different posttranslational modifications are involved in the generation of greater pathologic TDP-43 levels identified here in our cohort of cases with genetic expansions. These findings are consistent with emerging studies implicating distinct pathomechanisms in the generation of pathologic TDP-43 in cases with ALS with C9ORF72 or ATXN2 expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.
OBJECTIVE: To assess the amount of phosphorylated and nonphosphorylated TAR DNA-binding protein 43 (TDP-43) in the motor brain regions of cases of amyotrophic lateral sclerosis (ALS) with and without repeat expansions in the ATXN2 or C9ORF72 genes. METHODS: The 45-kDa phosphorylated form of TDP-43 and 43-kDa nonphosphorylated form of TDP-43 were quantified by immunoblot in postmortem brain tissue from the motor cortex, spinal cord, and cerebellar vermis of 23 cases with ALS with repeat expansions in the ATXN2 or C9ORF72 genes and sporadic disease and 10 controls. RESULTS: Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with C9ORF72 expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate ATXN2 expansions. In contrast, however, similar levels of nonphosphorylated TDP-43 were found in all 3 regions between ALS groups. CONCLUSION: Despite its central role in the pathogenesis of ALS and the emergence of potential targets to modify its aggregation, TDP-43 levels have not been quantified in pathologically confirmed cases with ALS. The present results demonstrating significant differences in phosphorylated but not nonphosphorylated TDP-43 levels suggest that different posttranslational modifications are involved in the generation of greater pathologic TDP-43 levels identified here in our cohort of cases with genetic expansions. These findings are consistent with emerging studies implicating distinct pathomechanisms in the generation of pathologic TDP-43 in cases with ALS with C9ORF72 or ATXN2 expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.
Authors: Matthew Nolan; Connor Scott; Menuka Pallebage Gamarallage; Daniel Lunn; Kilda Carpenter; Elizabeth McDonough; Dan Meyer; Sireesha Kaanumalle; Alberto Santamaria-Pang; Martin R Turner; Kevin Talbot; Olaf Ansorge Journal: Acta Neuropathol Commun Date: 2020-07-02 Impact factor: 7.801