From development to degeneration

Funding Information: This work was supported by National Institutes of Health Grants NS081674 and NS083378 to B.W., AG060285 to V.F., NS089737 and NS102780 to Q.C., and NS089578 to H.Z. S.M. was supported by National Institutes of Health Grant NS082619, the McCabe Fund Fellow Award, the University of Pennsylvania Alzheimer’s Disease Core Center, the Intellectual and Developmental Disabilities Research Center at the Children’s Hospital of Philadelphia and the University of Pennsylvania, and the Philadelphia Foundation. C.G.A. was supported by Maratona da Saude Award H2020/JPND (JPCOFUND/0004/2015-NAB3) and iNOVA4Health (UID/Multi/04462/2013, Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência/PT2020). Funding Information: Received Aug. 1, 2018; revised Sept. 17, 2018; accepted Sept. 20, 2018. ThisworkwassupportedbyNationalInstitutesofHealthGrantsNS081674andNS083378toB.W.,AG060285to V.F., NS089737 and NS102780 to Q.C., and NS089578 to H.Z. S.M. was supported by National Institutes of Health Grant NS082619, the McCabe Fund Fellow Award, the University of Pennsylvania Alzheimer’s Disease Core Center, the Intellectual and Developmental Disabilities Research Center at the Children’s Hospital of Philadelphia and the University of Pennsylvania, and the Philadelphia Foundation. C.G.A. was supported by Maratona da Saude Award H2020/JPND (JPCOFUND/0004/2015-NAB3) and iNOVA4Health (UID/Multi/04462/2013, Fundac¸ão para a Ciência e Tecnologia/Ministério da Educac¸ão e Ciência/PT2020). The authors declare no competing financial interests. Correspondence should be addressed to Dr. Huaye Zhang, Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.1665-18.2018 Copyright © 2018 the authors 0270-6474/18/389364-11$15.00/0 Publisher Copyright: © 2018 the authors. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.How do neurons adapt their endolysosomal system to address the particular challenge of membrane transport across their elaborate cellular landscape and to maintain proteostasis for the lifetime of the organism? Here we review recent findings that address this central question. We discuss the cellular and molecular mechanisms of endolysosomal trafficking and the autophagy pathway in neurons, as well as their role in neuronal development and degeneration. These studies highlight the importance of understanding the basic cell biology of endolysosomal trafficking and autophagy and their roles in the maintenance of proteostasis within the context of neurons, which will be critical for developing effective therapies for various neurodevelopmental and neurodegenerative disorders.publishersversionpublishe

Polarity Determinants in Dendritic Spine Development and Plasticity

The asymmetric distribution of various proteins and RNAs is essential for all stages of animal development, and establishment and maintenance of this cellular polarity are regulated by a group of conserved polarity determinants. Studies over the last 10 years highlight important functions for polarity proteins, including apical-basal polarity and planar cell polarity regulators, in dendritic spine development and plasticity. Remarkably, many of the conserved polarity machineries function in similar manners in the context of spine development as they do in epithelial morphogenesis. Interestingly, some polarity proteins also utilize neuronal-specific mechanisms. Although many questions remain unanswered in our understanding of how polarity proteins regulate spine development and plasticity, current and future research will undoubtedly shed more light on how this conserved group of proteins orchestrates different pathways to shape the neuronal circuitry

MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism

<div><p>The Par1 kinases, also known as microtubule affinity-regulating kinases (MARKs), are important for the establishment of cell polarity from worms to mammals. Dysregulation of these kinases has been implicated in autism, Alzheimer’s disease and cancer. Despite their important function in health and disease, it has been unclear how the activity of MARK/Par1 is regulated by signals from cell surface receptors. Here we show that MARK/Par1 is activated downstream of NMDA receptors in primary hippocampal neurons. Further, we show that this activation is dependent on protein kinase A (PKA), through the phosphorylation of Ser431 of Par4/LKB1, the major upstream kinase of MARK/Par1. Together, our data reveal a novel mechanism by which MARK/Par1 is activated at the neuronal synapse.</p></div