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Stable brain ATM message and residual kinase-active ATM protein in ataxia-telangiectasia
Jiali Li1, Jianmin Chen, Harry V Vinters
1Department of Cell Biology and Neuroscience, Nelson Biological Laboratories, Rutgers University, Piscataway, New Jersey 08854, USA. Jli@dls.rutgers.edu
Abstract:
The gene that is mutated in ataxia-telangiectasia (A-T), ATM, is catalytically activated in response to DNA damage. Yet a full accounting for the CNS deficits in human A-T or its mouse models remains elusive. We have analyzed the CNS phenotypes of two mouse Atm alleles--Atm(tm1Bal) (Bal) and Atm(tm1Awb) (Awb). Neither mutant has detectable mRNA or protein in peripheral tissues. In brain, although Bal/Bal mice have no ATM protein, they have nearly normal amounts of Atm mRNA. Bal/Bal neurons exhibit extensive cell cycle reentry and degeneration in both cortex and cerebellum. Unexpectedly, in Awb/Awb mice a novel mRNA is found in which the engineered mutation is excised. This mRNA is apparently translated and produces a catalytically active ATM protein that responds to DNA damage by phosphorylating p53 and Chk2. Prompted by these results, we examined eight cases of human A-T and found evidence for residual ATM protein in seven of them. These findings offer important new insights into the human disease and the role of brain ATM activity in the severity of the neurological symptoms of A-T.
Insights
Ataxia-telangiectasia (A-T) mouse models reveal that residual ATM protein in the brain, even if catalytically active, may influence neurological symptom severity. This finding offers new insights into human A-T disease mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Ataxia-telangiectasia (A-T) is a genetic disorder characterized by neurological deficits.
- The ATM gene is mutated in A-T and plays a role in DNA damage response.
- The precise contribution of ATM to central nervous system (CNS) deficits in A-T remains unclear.
Purpose of the Study:
- To investigate the central nervous system (CNS) phenotypes of two distinct mouse models with mutations in the Atm gene.
- To determine the presence and activity of ATM protein in mouse models and human A-T cases.
- To elucidate the relationship between ATM activity in the brain and the severity of neurological symptoms in A-T.
Main Methods:
- Analysis of CNS phenotypes in Atm(tm1Bal)/Atm(tm1Bal) and Atm(tm1Awb)/Atm(tm1Awb) mice.
- Detection of Atm mRNA and ATM protein in peripheral tissues and brain.
- Examination of ATM protein levels in eight human A-T patients.
Main Results:
- Atm(tm1Bal)/Atm(tm1Bal) mice lack ATM protein but retain Atm mRNA, exhibiting neuronal cell cycle reentry and degeneration in the cortex and cerebellum.
- Atm(tm1Awb)/Atm(tm1Awb) mice produce a novel, functional ATM protein from an excised mRNA, capable of phosphorylating p53 and Chk2 in response to DNA damage.
- Residual ATM protein was detected in seven out of eight human A-T cases.
Conclusions:
- The presence of catalytically active ATM protein, even from a novel mRNA transcript, can influence neurological phenotypes in mouse models.
- Residual ATM protein in human A-T patients suggests a potential role in disease severity.
- These findings provide critical new insights into the complex mechanisms underlying A-T neurological dysfunction.
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