Neuronal autophagy and neurodevelopmental disorders

Abstract

Neurodevelopmental disorders include a wide range of diseases such as autism spectrum disorders and mental retardation. Mutations in several genes that regulate neural development and synapse function have been identified in neurodevelopmental disorders. Interestingly, some affected genes and pathways in these diseases are associated with the autophagy pathway. Autophagy is a complex, bulky degradative process that involves the sequestration of cellular proteins, RNA, lipids, and cellular organelles into lysosomes. Despite recent progress in elucidating the genetics and molecular pathogenesis of these disorders, little is known about the pathogenic mechanisms and autophagy-related pathways involved in common neurodevelopmental disorders. Therefore, in this review, we focus on the current understanding of neuronal autophagy as well as recent findings on genetics and the roles of autophagy pathway in common neurodevelopmental disorders.

Keywords: autophagy; homeostasis; mTOR; neurodevelopment; neurodevelopmental disorders.

Fig. 1

Molecular components and signaling of autophagy. Autophagy begins with phagophore formation (isolation membrane). Initiation of phagophore formation is tightly regulated by various protein complexes. Under nutrient conditions, mTOR in the mTORC complex interacts with the ULK complex, thereby limiting its activity. mTOR is inhibited by autophagy induction conditon such as starvation, thereby activating the ULK complex, which in turn activates and translocates the PIK3C3 complex from microtubules to the ER. Beclin1, together with other components of the PIK3C3 complex such as Atg14, promotes PIK3C3 kinase activity. Activated PIK3C3 kinase generates PI3P, which in turn recruits WIPI1-4, VMP1, DFCP1, mATG2, and transmembrane mATG9 to nucleate the phagophore in close proximity to the cargo. Elongation of the phagophore to the limiting membrane around the cargo is regulated by the ATG5-ATG12-ATG16L1 and LC3-PE conjugation systems. ATG12 binds to ATG5, followed by ATG16L1 binding to form the ATG5-ATG12-ATG16L1 complex. LC3-PE complex formation is initiated by cleavage of LC3 by ATG4, followed by coordinated interactions with the ATG7, ATG3 (an E2 ligase), and ATG5-ATG12-ATG16L1 complex to generate LC3-PE on the phagophore membranes. The autophagosome then directly fuses with lysosomes for final degradation.

Fig. 2

Autophagy-related common pathway in neurodevelopmental disorders. Activation of PI3K-Atk signaling suppresses TSC1 and TSC2 complex leading to inactivation of Rheb (isoform of Ras superfamily) and release of mTOR from mTORC1 (mTOR complex 1). Dysfunctions of FMRP as a PIKE (PI3K enhancer) repressor in fragile X syndrome and TSC1/TSC2 as an mTOR repressor in tuberous sclerosis produce defects of neuronal development and synaptic plasticity with autistic behavioral phenotypes. In autism, mutations of PTEN (phosphatase and tensin homolog deleted on chromosome ten) also induce abnormal hyperactivity of PI3K/mTOR signaling pathway. Besides mTOR-dependent pathway, mTOR-independent pathway such as Epac2-Rap signaling affects neurite formation and autism phenotypes. Epac2, autism candidate gene RAPGEF4, is activated by cAMP binding and then changes an inactivated form to activated form of Rap which can regulate calpain via PLCε pathway. Neurofibromin encoded by NF1 normally leads to inactivation of Ras. However, mutations of neurofibromin in Neurofibromatosis 1 causes overactivation of Ras/ERK and PI3K signaling, leading to inactivation of TSC1/TSC2 complex and release of mTOR from Rheb suppression.