Molecular Mechanisms of Neurodegeneration in Ataxia Telangiectasia: The Role of ATM and DNA Damage Response Pathways

 

Ataxia telangiectasia (AT) is an inherited, neurodegenerative disease which is often diagnosed in children. This disease is caused due to the mutations in the ATM ( ataxia telangiectasia mutated) gene located in chromosome 11. It causes uncoordinated or ataxia movements with dilated blood vessels of the eye (ocular telangiectasia), loss of cerebellar function, and speech defects along with thinning of molecular layers of cerebellum and cerebellar atrophy. Other features that represent this disease are immune deficiency (absence of IgA, IgG2 and IgE), sterility, lymphoid cancer, and radiosensitivity. The patients with AT mostly die because of pneumonia, or chronic lung disease due to the compromised immune condition. 

The understanding of the ATM gene’s role in the AT was the biggest breakthrough as it has facilitated rapid molecular diagnosis. ATM, which is a large protein, has sequence homology with a family of proteins that are related to phosphatidylinositol‐3‐OH‐kinases (PI(3)K).  It has about 66 exons that results in a mRNA of 12 kb that encodes a protein of 350 Da. Some mutations produce decreased amounts of  functional genes, hence reducing the severity of the disease. 
  
The ATM is first in response to the DNA double-stranded breaks, telomere maintenance, immune response, cellular response. Hypomorphic mutations in the MRN complex (three proteins of MRE11, RAD50 and NBS1) result in the similarity of two syndromes; Nijmegen breakage syndrome and AT‐like disorder. Since the ATM gene regulates the cell-cycle, when there is a damaged DNA checked by defective cell-cycle checkpoint they lead to defective phosphorylation of ATM substrates.

It is crucial to understand the dysfunction of the nervous system as AT is characterized by neurodegeneration. Because of compromised DNA damage responses it leads to neurodegeneration. DNA repair proteins like Lig4 and XRCC4 are important for brain development and the deletion of these genes can lead to neurodegeneration. To avoid accumulation of genetic lesions, cell death is triggered by the ATM in the nervous system, failing to do so will  result in long-term cellular dysfunction and contribute to neurodegeneration.

Genomic instability and defects in DNA damage responses in individuals like people with AT are prone to cancer. About 10% of AT patients develop cancer, mostly leukemia or lymphoma because of the defective response in DNA double-stranded breaks.  ATM heterozygotes have an increased risk of cancer. In sporadic cancers like leukemia somatic mutations of ATM can be found. 

ATLD is an AT-like disorder that is caused due to the mutation in the MER11 gene. As the name suggests ATLD shares similarities with AT although the former is less severe. ATM substrates like p53 and CHK2 can be activated by the MRN complex depending on the protein composition. It can also lead to increased oxidative stress in the nervous system due to ATM deficiency. Nijmegen Breakage Syndrome (NBS), which is almost similar to AT but causes microcephaly is caused by the mutation in of the ATM substrate, NBS1.  

Due to the challenges in understanding the neural tissues, neurodegeneration in AT is difficult to understand. Ataxia-ocular apraxia 1, are similar neurodegenerative diseases that are linked to defective DNA damage responses. Despite the discovery of ATM 'S viral role in Ataxia telangiectasia there are many questions for which answers have not been found and understanding tissue-specific ATM functions will provide crucial insights. 

REFERENCE

McKinnon PJ. ATM and ataxia telangiectasia: second in molecular medicine review series. EMBO reports. 2004 Aug 1;5(8):772-6.

IMAGE REFERENCE

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