E3 ubiquitin ligase와 신경퇴화

Reference: E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration (Front. Mol. Neurosci., 2017)

https://doi.org/10.3389/fnmol.2017.00151

E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration

@Subtitles

- Neurodevelopmental Processes And Neurodegenerative Diseases Are Affected By Environmental And Genetic Factors

- Good Programming Of Ube3a: How It Is Important For Neuronal Development And Neurodegeneration?

-Accurate And Wide Spread Functions Of Aip4 Gene Product Orients Neuronal Development And Survival

-Mgrn1 Ultra-Compact Neuronal Functions Clean-Up Overload Of Unwanted Accumulation Of Abnormal Proteins, And Implications In Neuronal Developmental Disorders And Neurodegeneration

-Hace1 E3 Ubiquitin Ligase: Efforts Against Neurodevelopmental Disorders And Neurodegenerative Diseases

-E3 Ubiquitin Ligases Are Crucial For Brain Development And Their Aberrant Functions Are Fatal

-E3 Ubiquitin Ligases: Possible Emerging Molecular Functions, Targets, And Therapeutic Applications

 

Fig1. An illustration of the orchestration of factors involved in neurodevelopment and neurodegeneration: The upper part of the figure represents how stepwise modifications occur during the prenatal period of brain development. As described in respective sections of the text, few crucially important genes, which play pivotal roles at various stages of brain development, have been mentioned at the top. To establish a better understanding, schematic of cellular translation machinery along with other PQC systems has also been drawn. A state of proteostasis and active control of PQC system regulate the processes of growth, adolescence, and development. However, aging related metabolic changes, including various kinds of stresses and successive deterioration of quality control systems may lead to accumulation of several proteins, causing the formation of inclusion bodies, which results in late-stage neurodegeneration. Few important established protein candidates, involved in various such diseases have been mentioned at the bottom panel; for details, please refer text.

 

Fig2. Schematic representation of emerging roles of neurobiological QC E3 ubiquitin ligases implicated in neurodevelopment, synaptogenesis, and, their lack of functions contribute to the pathogenesis of neurodegeneration: (A) Genetic defects in UBE3A gene results in defective E6-AP protein, which is responsible for Angelman syndrome neurodevelopmental disorder. Functional E6-AP promotes the ubiquitylation of tumor-suppressor proteins such as p53 and p27 and regulates cellular proliferation and growth. E6-AP also plays a significant role in the clearance of mutant misfolded proteins linked with various neurodegenerative diseases. (B) ITCH specifically ubiquitylates several cytoplasmic protein inclusions for their removal from the dense crowded cellular milieu. The central segment represents overall functional roles of QC E3 ubiquitin ligases due to their crucial involvement in the neurodevelopment and neurodegeneration. (C) Mahogunin functions as a RING finger E3 ubiquitin ligase; and a null mutation in mahogunin is linked with spongiform neurodegeneration. Our studies reveal the potential roles of MGRN1 as a QC E3 ubiquitin ligase involved in the elimination of mutated proteins linked with polyglutamine and ALS neurodegenerative diseases.

 

Fig3. Proposed diagrammatic representations comprehend the neurobiological roles of few E3 ubiquitin ligases associated with normal brain development. The complex molecular mechanisms governed by these E3 ubiquitin ligases throughout the entire life span starting from learning skills (neurodevelopment) to kills (neurodegeneration) are still unknown.