E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration

Abstract

Cells regularly synthesize new proteins to replace old or damaged proteins. Deposition of various aberrant proteins in specific brain regions leads to neurodegeneration and aging. The cellular protein quality control system develop various defense mechanisms against the accumulation of misfolded and aggregated proteins. The mechanisms underlying the selective recognition of specific crucial protein or misfolded proteins are majorly governed by quality control E3 ubiquitin ligases mediated through ubiquitin-proteasome system. Few known E3 ubiquitin ligases have shown prominent neurodevelopmental functions, but their interactions with different developmental proteins play critical roles in neurodevelopmental disorders. Several questions are yet to be understood properly. How E3 ubiquitin ligases determine the specificity and regulate degradation of a particular substrate involved in neuronal proliferation and differentiation is certainly the one, which needs detailed investigations. Another important question is how neurodevelopmental E3 ubiquitin ligases specifically differentiate between their versatile range of substrates and timing of their functional modulations during different phases of development. The premise of this article is to understand how few E3 ubiquitin ligases sense major molecular events, which are crucial for human brain development from its early embryonic stages to throughout adolescence period. A better understanding of these few E3 ubiquitin ligases and their interactions with other potential proteins will provide invaluable insight into disease mechanisms to approach toward therapeutic interventions.

Keywords: E3 ubiquitin ligases; aging; neurodegenerative diseases; neurodevelopmental disorders; neurons.

FIGURE 1

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.

FIGURE 2

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.

FIGURE 3

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.