ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size

Abstract

Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size.

Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

“…In the central nervous system with its specialized long-lived cells characterized by extensive membrane processes, in addition to its traditional role in maintaining cellular homeostasis (Hu et al, 2015;Tooze and Schiavo, 2008), autophagy plays several other roles: the modulation of synaptic plasticity (Hernandez et al, 2012), the maintenance of the pool of neural stem cells required for postnatal neurogenesis (Wang et al, 2013), and finally, the normal development of the CNS, including neural progenitor proliferation, neuronal maturation, connectivity and myelination (Ban et al, 2013;Hara et al, 2006;Jang et al, 2015;Kadir et al, 2016;Kim et al, 2016;Komatsu et al, 2006;Liang et al, 2010;Rangaraju et al, 2010;Schwarz et al, 2012;Smith et al, 2013;Song et al, 2008). As could be expected, defects in autophagy-related genes or dysfunctions of autophagy are reflected in a number of human neurological disorders (for review, see (Bockaert and Marin, 2015;Ebrahimi-Fakhari et al, 2016;Yamamoto and Yue, 2014)).…”

Zika virus infection during pregnancy and induced brain pathology in beclin1-deficient mouse model

“…Reduction in Beclin1 or impaired autophagy enhanced ZIKV-R103451 (but not other strains)-mediated pathology in in-utero exposed pups; suggesting a ZIKV strain specific effect of autophagy pathway in associated pathologies. Beclin1 and the ultraviolet irradiation resistance-associated gene (UVRAG) are involved in both autophagy and centrosome stability and linked to ZIKV mediated microcephaly (36, 37), while the recently identified MCPH18, a phosphatidylinositol 3-phosphate-binding protein, functions as a scaffold protein for autophagic removal of aggregated protein; suggesting a potential link of autophagy in the development of primary microcephaly (38). Autophagy is a common pathway involved in regulating the replication of ZIKV as well as other viral-infections in cells of the central nervous system (13, 17, 39–43).…”

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

“…2. Two loci encode structural components of global cellular machineries, which act respectively in the build-up of the Golgi (MCPH19, or COPB2) [10] and in the autophagic process (MCPH18, or WDFY3) [11], encoding a phosphatidylinositol 3-phosphate-binding protein.…”