RESUMEN
The genetics of human disease serves as a robust and unbiased source of insight into human biology, both revealing fundamental cellular processes and exposing the vulnerabilities associated with their dysfunction. Over the last decade, the genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have epitomized this concept, as studies of ALS-FTD-causing mutations have yielded fundamental discoveries regarding the role of biomolecular condensation in organizing cellular contents while implicating disturbances in condensate dynamics as central drivers of neurodegeneration. Here we review this genetic evidence, highlight its intersection with patient pathology, and discuss how studies in model systems have revealed a role for aberrant condensation in neuronal dysfunction and death. We detail how multiple, distinct types of disease-causing mutations promote pathological phase transitions that disturb the dynamics and function of ribonucleoprotein (RNP) granules. Dysfunction of RNP granules causes pleiotropic defects in RNA metabolism and can drive the evolution of these structures to end-stage pathological inclusions characteristic of ALS-FTD. We propose that aberrant phase transitions of these complex condensates in cells provide a parsimonious explanation for the widespread cellular abnormalities observed in ALS as well as certain histopathological features that characterize late-stage disease.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Condensados Biomoleculares/química , Gránulos de Ribonucleoproteínas Citoplasmáticas/química , Demencia Frontotemporal/genética , Proteínas de Unión al ARN/química , ARN/química , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Sitios de Unión , Condensados Biomoleculares/metabolismo , Muerte Celular/genética , Gránulos de Ribonucleoproteínas Citoplasmáticas/genética , Gránulos de Ribonucleoproteínas Citoplasmáticas/metabolismo , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Humanos , Simulación de Dinámica Molecular , Mutación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Transición de Fase , Unión Proteica , ARN/genética , ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismoRESUMEN
SYNCRIP, a member of the cellular heterogeneous nuclear ribonucleoprotein (hnRNP) family of RNA binding proteins, regulates various aspects of neuronal development and plasticity. Although SYNCRIP has been identified as a component of cytoplasmic RNA granules in dendrites of mammalian neurons, only little is known about the specific SYNCRIP target mRNAs that mediate its effect on neuronal morphogenesis and function. Here, we present a comprehensive characterization of the cytoplasmic SYNCRIP mRNA interactome using iCLIP in primary rat cortical neurons. We identify hundreds of bona fide SYNCRIP target mRNAs, many of which encode for proteins involved in neurogenesis, neuronal migration and neurite outgrowth. From our analysis, the stabilization of mRNAs encoding for components of the microtubule network, such as doublecortin (Dcx), emerges as a novel mechanism of SYNCRIP function in addition to the previously reported control of actin dynamics. Furthermore, we found that SYNCRIP synergizes with pro-neural miRNAs, such as miR-9. Thus, SYNCRIP appears to promote early neuronal differentiation by a two-tier mechanism involving the stabilization of pro-neural mRNAs by direct 3'UTR interaction and the repression of anti-neural mRNAs in a complex with neuronal miRISC. Together, our findings provide a rationale for future studies investigating the function of SYNCRIP in mammalian brain development and disease.
