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

Abstract

A screen for neuroprotective genes in Drosophila melanogaster 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 brain tumor (brat) 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 brat in the adult Drosophila brain has not been described previously. The new allele, bratcheesehead (bratchs), 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 bratchs 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 brat that could be relevant to human cancer and neurodegenerative diseases.

The Role of Dynamic miRISC During Neuronal Development

“…All these studies indicate that it is not miRNA alone, but the composition of miRISC has a great significance in the pathophysiology of disorders of the nervous system. There is Bhattacharyya, 2016, 2018) FMRP (Castren et al, 2005;Tervonen et al, 2009;Callan et al, 2010;Saffary and Xie, 2011;Jeon et al, 2014) TRIM-32 (Brat, mei-P26,NHL-2) (Bello, 2006;Betschinger et al, 2006;Lee et al, 2006;Bowman et al, 2008;Neumüller et al, 2008;Hammell et al, 2009;Schwamborn et al, 2009;Loewen et al, 2018) Hu Proteins (Marusich et al, 1994;Dobashi et al, 1998;Kasashima et al, 1999;Anderson et al, 2000;Akamatsu et al, 2002Akamatsu et al, , 2005Perrone-Bizzozero and Bolognani, 2002;Kraushar et al, 2014) Pumilio (Burow et al, 2015;Zahr et al, 2018) ESCRT Factors FMRP (Dockendorff et al, 2002;Ivanco and Greenough, 2002;Morales et al, 2002;Michel, 2004;Pan et al, 2004;Li, 2009;Doll and Broadie, 2015;Wang et al, 2015;Zimmer et al, 2017;Shen et al, 2019) MOV10 (Skariah et al, 2017) Pumilio (Menon et al, 2004(Menon et al, , 2009Ye et al, 2004;Vessey et al, 2010;...…”

Modeling Neurodegenerative Disorders in Drosophila melanogaster

“…A novel genetic model for neurodegeneration recently was described in Drosophila [166] (Table 7). This model consists of a new mutation in the TRIM-NHL (tripartite motif-NCL-1, HT2A, and LIN-41) protein encoded by the Drosophila brain tumor (brat) gene.…”

Neural stem cell dynamics: the development of brain tumours

“…[32][33][34]. Intriguingly, a recent study has suggested that the decision for INPs to differentiate or revert to NSC fate in certain brat mutants could be stochastic [35]. The majority of the proliferating cells in these tumours are not type II neuroblasts but are likely INPs that maintain the ability to self-renew and produce neurons and glia [35].…”