ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

Pizzamiglio, Lara; Focchi, Elisa; Antonucci, Flavia

doi:10.3390/cells9091969

Cited by 22 publications

(15 citation statements)

References 175 publications

(203 reference statements)

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“…However, ATM also activates several proteins that function in other cellular pathways. For example, ATM is also a regulator of mitophagy, oxidative stress responses and insulin signaling [ 36 , 37 ]. DNA-PKcs is activated by the Ku70/Ku80-DNA complex and is required for NHEJ [ 13 , 38 ].…”

Section: Dna Damage Response and Repair Mechanismsmentioning

confidence: 99%

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Gupta

You

SenGupta

et al. 2021

Biology

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Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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Section: Dna Damage Response and Repair Mechanismsmentioning

confidence: 99%

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Gupta

You

SenGupta

et al. 2021

Biology

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“…If this fails, the cell becomes senescent or is directed to a programmable death pathway, usually apoptosis. Therefore, DDR may differ in mitotic and postmitotic cells, and this is likely responsible for different AT phenotypes in different tissues: loss of ATM-mediated signaling in mitotic cells results in cancer(s), but in postmitotic neurons—in degeneration [ 80 , 81 ]. In addition, in mitotic cells, DDR may tolerate or misrepair some DNA damages to preserve the process of replication.…”

Section: The Aging Stress Responsementioning

confidence: 99%

The Aging Stress Response and Its Implication for AMD Pathogenesis

Błasiak

Pawłowska

Sobczuk

et al. 2020

IJMS

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Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

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“…ATM's role in DNA repair is also implicated in normal immune system development, where it is proposed to contribute to the recombination of natural DNA splicing that occurs during gene rearrangement in T-and B-lymphocyte maturation (Chao, Yang, and Xu 2000;Matei, Guidos, and Danska 2006;Vacchio et al 2007;Schubert, Reichenbach, and Zielen 2002). Although its roles are still emerging, ATM has also been implicated in oxidative stress homeostasis (Guo et al 2010) and mitophagy (Valentin-Vega and Kastan 2012;Pizzamiglio, Focchi, and Antonucci 2020).…”

Section: Introductionmentioning

confidence: 99%

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

Perez

Abdallah

Chavira

et al. 2021

eLife

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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 are 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 (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal’s first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

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ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

Cited by 22 publications

References 175 publications

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

The Aging Stress Response and Its Implication for AMD Pathogenesis

A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation

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