OBJECTIVE: To develop a human in vitro model of Ataxia Telangiectais (A-T) for efficient screenin... more OBJECTIVE: To develop a human in vitro model of Ataxia Telangiectais (A-T) for efficient screening of novel therapeutic compounds. BACKGROUND: Ataxia Telangiectasia (A-T) is an early onset progressive neurodegenerative disease caused by loss of function mutations in ATM. ATM protein is a kinase that plays a crucial role in cellular response to double stranded-DNA break. Thus far, animal models of A-T have failed to show many aspects of the disease, including progressive cerebellar ataxia, the most debilitating symptom in A-T patients. DESIGN/METHODS: Using lenti-virus that harbors reprogramming Yamanaka factors, we reprogrammed A-T patient9s fibroblasts into induced pluripotent stem cells (iPSC). These iPSCs were characterized for their pluripotency by immunostaining and teratoma assay. These iPSCs were then differentiated into neural lineages, including neuroprogenitor and neurons. These neural derivatives were subjected to gamma irradiation to induce double-stranded DNA break. ATM...
Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurolog... more Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders is severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons are significantly perturbed (e.g., reduced membrane capacitance, lower action potential threshol...
OBJECTIVE: To develop a human in vitro model of Ataxia Telangiectais (A-T) for efficient screenin... more OBJECTIVE: To develop a human in vitro model of Ataxia Telangiectais (A-T) for efficient screening of novel therapeutic compounds. BACKGROUND: Ataxia Telangiectasia (A-T) is an early onset progressive neurodegenerative disease caused by loss of function mutations in ATM. ATM protein is a kinase that plays a crucial role in cellular response to double stranded-DNA break. Thus far, animal models of A-T have failed to show many aspects of the disease, including progressive cerebellar ataxia, the most debilitating symptom in A-T patients. DESIGN/METHODS: Using lenti-virus that harbors reprogramming Yamanaka factors, we reprogrammed A-T patient9s fibroblasts into induced pluripotent stem cells (iPSC). These iPSCs were characterized for their pluripotency by immunostaining and teratoma assay. These iPSCs were then differentiated into neural lineages, including neuroprogenitor and neurons. These neural derivatives were subjected to gamma irradiation to induce double-stranded DNA break. ATM...
Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurolog... more Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders is severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons are significantly perturbed (e.g., reduced membrane capacitance, lower action potential threshol...
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Papers by Kotoka Nakamura