Skip to main content

The Cytoplasmic Function of Atm in Neurons: Beyond DNA Breaks

The Ataxia-telangiectasia mutated protein kinase (ATM) is traditionally known for its role in DNA damage response, particularly in sensing and repairing DNA double-strand breaks. However, recent research has uncovered novel cytoplasmic functions of ATM in neurons that extend beyond its canonical role in DNA repair. Here are some key points regarding the cytoplasmic function of ATM in neurons:


1.      Regulation of Nucleolar Transcription:

o  ATM Activation: In neurons, ATM has been identified as a regulator of RNA-Polymerase-1 (Pol-1)-mediated transcription of nucleolar rRNA genes (rDNA). Activation of ATM, even at low concentrations of DNA double-strand break inducers, stimulates rDNA transcription in cortical neurons.

o    Transcriptional Regulation: ATM positively regulates nucleolar transcription by modulating the activity of Pol-1, which is essential for ribosomal RNA synthesis and ribosome biogenesis. Dysregulation of nucleolar transcription due to ATM deficiency may contribute to neurodegenerative processes.

2.     Nucleolar Localization:

o ATM Localization: Interestingly, ATM has been found to be robustly present in neuronal nucleoli, the subnuclear compartments responsible for ribosome biogenesis. This localization suggests a direct role for ATM in regulating nucleolar functions and ribosomal biogenesis in neurons.

o    Phosphorylation Targets: Critical regulators of Pol-1, the enzyme responsible for rRNA synthesis, display potential ATM phosphorylation sites. This indicates that ATM may directly modulate the activity of nucleolar transcription factors to regulate ribosomal biogenesis.

3.     Neurodegenerative Implications:

o Defective Ribosomal Biogenesis: Dysregulation of nucleolar transcription and ribosome biogenesis, as observed in ATM-deficient neurons, may contribute to neurodegenerative processes. Impaired ribosomal biogenesis can lead to disruptions in protein synthesis, cellular homeostasis, and neuronal function, potentially exacerbating neurodegenerative conditions.

o ATM-Related Disorders: Mutations in the ATM gene are associated with Ataxia-telangiectasia (A-T), a neurodegenerative disorder characterized by progressive cerebellar degeneration and increased cancer susceptibility. The cytoplasmic functions of ATM in nucleolar transcription provide insights into the pathophysiology of A-T and related neurodegenerative conditions.

4.    Therapeutic Implications:

o Targeting Nucleolar Transcription: Modulating nucleolar transcription and ribosome biogenesis pathways regulated by ATM could offer novel therapeutic strategies for neurodegenerative disorders associated with ATM dysfunction. Targeting ribosomal biogenesis processes may help restore neuronal homeostasis and function in these conditions.

o    Precision Medicine Approaches: Understanding the cytoplasmic functions of ATM in neurons opens up avenues for precision medicine approaches that target nucleolar transcription pathways specifically in neurodegenerative disorders linked to ATM abnormalities. Tailored interventions aimed at restoring nucleolar function could hold promise for disease management.

In conclusion, the cytoplasmic function of ATM in neurons, particularly its role in regulating nucleolar transcription and ribosomal biogenesis, represents a novel aspect of ATM biology beyond its canonical DNA damage response functions. Dysregulation of ATM-mediated nucleolar processes may contribute to neurodegenerative conditions, highlighting the therapeutic potential of targeting these pathways in neuronal disorders.

 

Comments

Popular posts from this blog

How do pharmacological interventions targeting NMDA glutamate receptors and PKCc affect alcohol drinking behavior in mice?

Pharmacological interventions targeting NMDA glutamate receptors and PKCc can have significant effects on alcohol drinking behavior in mice. In the context of the study discussed in the PDF file, the researchers investigated the impact of these interventions on ethanol-preferring behavior in mice lacking type 1 equilibrative nucleoside transporter (ENT1). 1.   NMDA Glutamate Receptor Inhibition : Inhibition of NMDA glutamate receptors can reduce ethanol drinking behavior in mice. This suggests that NMDA receptor-mediated signaling plays a role in regulating alcohol consumption. By blocking NMDA receptors, the researchers were able to observe a decrease in ethanol intake in ENT1 null mice, indicating that NMDA receptor activity is involved in the modulation of alcohol preference. 2.   PKCc Inhibition : Down-regulation of intracellular PKCc-neurogranin (Ng)-Ca2+-calmodulin dependent protein kinase type II (CaMKII) signaling through PKCc inhibition is correlated with reduced CREB activity

How the Neural network circuits works in Parkinson's Disease?

  In Parkinson's disease, the neural network circuits involved in motor control are disrupted, leading to characteristic motor symptoms such as tremor, bradykinesia, and rigidity. The primary brain regions affected in Parkinson's disease include the basal ganglia and the cortex. Here is an overview of how neural network circuits work in Parkinson's disease: 1.      Basal Ganglia Dysfunction: The basal ganglia are a group of subcortical nuclei involved in motor control. In Parkinson's disease, there is a loss of dopamine-producing neurons in the substantia nigra, leading to decreased dopamine levels in the basal ganglia. This dopamine depletion results in abnormal signaling within the basal ganglia circuitry, leading to motor symptoms. 2.      Cortical Involvement: The cortex, particularly the motor cortex, plays a crucial role in initiating and coordinating voluntary movements. In Parkinson's disease, abnormal activity in the cortex, especially in the beta and gamma

Force-Velocity Relationship

The force-velocity relationship in muscle physiology describes how the force a muscle can generate is influenced by the velocity of muscle contraction. Here are key points regarding the force-velocity relationship: 1.     Inverse Relationship : o     The force-velocity relationship states that the force a muscle can generate is inversely related to the velocity of muscle shortening. o     At higher contraction velocities (faster shortening), the force-generating capacity of the muscle decreases. o     Conversely, at lower contraction velocities (slower shortening), the muscle can generate higher forces. 2.     Factors Influencing Force-Velocity Relationship : o     Cross-Bridge Cycling : The rate at which cross-bridges form and detach during muscle contraction affects the force-velocity relationship. At higher velocities, there is less time for cross-bridge formation, leading to reduced force production. o     Energy Availability : The availability of ATP, which powers muscle contracti

How can a better understanding of the physical biology of brain development contribute to advancements in neuroscience and medicine?

A better understanding of the physical biology of brain development can significantly contribute to advancements in neuroscience and medicine in the following ways: 1.    Insights into Neurodevelopmental Disorders:  Understanding the role of physical forces in brain development can provide insights into the mechanisms underlying neurodevelopmental disorders. By studying how disruptions in mechanical cues affect brain structure and function, researchers can identify new targets for therapeutic interventions and diagnostic strategies for conditions such as autism, epilepsy, and intellectual disabilities. 2.   Development of Novel Treatment Approaches:  Insights from the physical biology of brain development can inspire the development of novel treatment approaches for neurological disorders. By targeting the mechanical aspects of brain development, such as cortical folding or neuronal migration, researchers can design interventions that aim to correct abnormalities in brain structure and

Complex Random Sampling Designs

Complex random sampling designs refer to sampling methods that involve a combination of various random sampling techniques to select a sample from a population. These designs often incorporate elements of both probability and non-probability sampling methods to achieve specific research objectives. Here are some key points about complex random sampling designs: 1.     Definition : o     Complex random sampling designs involve the use of multiple random sampling methods, such as systematic sampling, stratified sampling, cluster sampling, etc., in a structured manner to select a sample from a population. o     These designs aim to improve the representativeness, efficiency, and precision of the sample by combining different random sampling techniques. 2.     Purpose : o    The primary goal of complex random sampling designs is to enhance the quality of the sample by addressing specific characteristics or requirements of the population. o     Researchers may use these designs to increase