in-vivo-forward-genetic-screen-to-identify-novel-neuroprotective

In Vivo Forward Genetic Screen to Identify Novel Neuroprotective Genes in <em>Drosophila melanogaster</em>

There is much to understand about the onset and progression of neurodegenerative diseases, including the underlying genes responsible. Forward genetic ...

University of Alabama

Increasing body of evidence indicates that proper glial function plays an important role in neuroprotection and in organismal physiology throughout lifespan. Work done in the model organism  has revealed important aspects of glial cell biology in the contexts of longevity and neurodegeneration. In this mini review, we summarize recent findings from work done in the fruit fly  about the role of glia in maintaining a healthy status during animal's life and discuss the involvement of glial innate immune pathways in lifespan and neurodegeneration. Overactive nuclear factor kappa B (NF-κB) pathways and defective phagocytosis appear to be major contributors to lifespan shortening and neuropathology. Glial NF-κB silencing on the other hand, extends lifespan possibly through an immune-neuroendocrine axis. Given the evolutionary conservation of NF-κB innate immune signaling and of macrophage ontogeny across fruit flies, rodents, and humans, the above observations in glia could potentially support efforts for therapeutic interventions targeting to ameliorate age-related pathologies.

Role of Glial Immunity in Lifespan Determination: A  Perspective.

A screen for neuroprotective genes in  led to the identification of a mutation that causes extreme, progressive loss of adult brain neuropil in conjunction with massive brain overgrowth. We mapped the mutation to the  () locus, which encodes a tripartite motif-NCL-1, HT2A, and LIN-41 (TRIM-NHL) RNA-binding protein with established roles limiting stem cell proliferation in developing brain and ovary. However, a neuroprotective role for  in the adult  brain has not been described previously. The new allele,  ( ), carries a mutation in the coiled-coil domain of the TRIM motif, and is temperature-sensitive. We demonstrate that mRNA and protein levels of neural stem cell genes are increased in heads of adult  mutants and that the over-proliferation phenotype initiates prior to adult eclosion. We also report that disruption of an uncharacterized gene coding for a presumptive prolyl-4-hydroxylase strongly enhances the over-proliferation and neurodegeneration phenotypes. Together, our results reveal an unexpected role for  that could be relevant to human cancer and neurodegenerative diseases.

A Novel Mutation in Brain Tumor Causes Both Neural Over-Proliferation and Neurodegeneration in Adult .

Innate immunity is the first line of defense against invading pathogens and plays an essential role in defending the brain against infection, injury, and disease. It is currently well recognized that central nervous system (CNS) infections can result in long-lasting neurological sequelae and that innate immune and inflammatory reactions are highly implicated in the pathogenesis of neurodegeneration. Due to the conservation of the mechanisms that govern neural development and innate immune activation from flies to mammals, the lack of a classical adaptive immune system and the availability of numerous genetic and genomic tools, the fruit fly  presents opportunities to investigate the cellular and molecular mechanisms associated with immune function in brain tissue and how they relate to infection, injury and neurodegenerative diseases. Here, we present an overview of currently identified innate immune mechanisms specific to the adult  brain.

Article	Year
Role of Glial Immunity in Lifespan Determination: A Perspective. Frontiers in immunology\| PubMed ID: 29942319	2018
A Novel Mutation in Brain Tumor Causes Both Neural Over-Proliferation and Neurodegeneration in Adult . G3 (Bethesda, Md.)\| PubMed ID: 30126833	2018
as a Model to Study Brain Innate Immunity in Health and Disease. International journal of molecular sciences\| PubMed ID: 30544507	2018

Stanislava Chtarbanova

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