Autophagy Defciency in Neurodevelopmental Disorders Part 2

Complex developmental disorders

WIPI2, the mammalian homolog of the yeast Atg18, is a key regulator of autophagy. WIPI2 interacts with ATG16L1 and recruits the ATG12-ATG5-ATG16L1 complex to the phagophore and therefore promotes LC3 lipidation and subsequent autophagosome formation [25]. 

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By performing whole exome sequencing on affected individuals with complex developmental disorders including mental retardation, speech, and language impairment, as well as other neurological and psychiatric abnormalities, a recent study identified a novel nonsynonymous homozygous mutation (V249M) in the WIPI2 gene [26]. 

The same study reported that V231M mutation on WIPI2b (corresponding to V249M in WIPI2a) significantly reduced its interaction with ATG16L1 and ATG5-12 complex [26]. Compared to the controls, the fibroblasts derived from the patients carrying the V249M mutation show reduced LC3 lipidation, which is correlated to the reduced WIPI2 puncta, and subsequent reduced level of autophagy flux [26]. 

The results imply that the impairment of autophagosome formation may cause neurodevelopmental disorders. In line with this notion, by performing whole exome sequencing on a family in which one of four children displays severe cortical atrophy, intellectual impairment, ataxia, and other neurological symptoms, Keays et al. identified a single homozygous coding mutation (L1224R) in VPS15 in an affected case [27]. 

VPS15 is a key component in the VPS15-VPS34-Beclin1 complex which plays a critical role in autophagosome formation. The experiments performed by Keays et al. demonstrate that compared to controls, the dermal fibroblasts derived from affected individuals show reduced protein levels of VPS15, VPS34, and Beclin1, decreased LysoTracker staining, and increased protein level of p62, an autophagy cargo receptor [27]. 

Further study indicates that ectopic expression of wild-type VPS15 in L1224R patient cells increases the protein levels of VPS15, stabilizes VPS34 and Beclin1, and decreases the protein level of p62 [27]. 

These findings indicate that the L1224R mutation in VPS15 is associated with human neurodevelopmental disorders by compromising the function of the VPS15- VPS34-Beclin1 complex in autophagy. ATG7 is an essential effector enzyme for canonical autophagy. 

Most recently, by performing genetic and clinical analysis, Taylor et al. identified recessive and loss-of-function mutations in both ATG7 alleles in 12 individuals from five unrelated families, which exhibit complex neurodevelopmental disorders including ataxia and developmental delay [15]. 

Experiments conducted in the fibroblasts and skeletal muscles derived from the patients indicate that the expression of ATG7 is diminished or absent in patients-derived cells, resulting in impaired LC3 lipidation and autophagy flux [15]. 

The functional complementation experiments in mice and yeast confirmed the functional deficiencies induced by the missense variants in ATG7 [15]. Taken together, the study reveals the critical role of basal autophagy in human neural development and integrity.

Autophagy dysregulation in neurodevelopmental disorders

Growing evidence indicates the dysregulation of mTOR in ASD [28–30]. mTOR is a central regulator of diverse cellular processes including autophagy. mTOR is negatively regulated by tuberous sclerosis complex 1/2 (TSC1/2) [16, 31, 32]. 

Previous studies reported that the TSC2± mice display constitutive hyperactivity of mTOR, blockade of autophagy, and consequent spine pruning defects [33]. Moreover, an mTOR inhibitor rapamycin can correct the spine pruning defects and ASD-relevant behaviors in TSC2± mice, but not in TSC2±:ATG7 cKO mice [33]. 

A most recent study has reported similar results in parvalbumin (PV) cell-restricted TSC1 conditional haploinsufficient and knockout mice, which show transient autophagy dysfunctions, a loss of perisomatic innervation, and social behavior deficits [34]. 

Moreover, treatment with rapamycin in a sensitive period rescues PV cell connectivity and social behavior in TSC1 conditional haploinsufficient mice [34]. Apart from TSC1/2 models of ASD, recent studies have reported the impaired expression of autophagy-related protein Beclin1 in animal models of ASD including Cc2d1a± and ADNP± mice [35, 36]. 

These studies indicate that dysregulation of autophagy may contribute to neuronal pathology and aberrant social behaviors in ASD. Fragile X syndrome (FXS), a leading genetic cause of autism, is a heritable form of intellectual disability including autistic behaviors, attentional deficits, emotional lability, impaired cognition, and other neurological disabilities [37–39]. 

Fragile X mental retardation (Fmr1) is a causative gene to FXS [40]. Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene, is an RNA-binding protein that tightly regulates the function of multiple neuronal mRNAs critical to neuronal development and synaptic plasticity [41, 42]. Fmr1-KO mice are a well-characterized model of FXS [40]. 

Previous studies have reported the dysregulation of mTOR signaling in FXS mice and humans with FXS [43, 44]. A recent study demonstrates that the biochemical markers of autophagy such as LC3II puncta, the active form of p-ULK1 and p-Beclin1, and consequent autophagy flux are significantly reduced, while p62 is accumulated, in the hippocampal neurons of Fmr1-KO mice, perhaps as a result of deregulated mTOR signaling [45]. 

Mechanistic investigations indicate that the mTORC1 activity is enhanced and Raptor, a defining component of mTORC1, translocates to the lysosome [45]. And specific knockdown of Raptor in the hippocampal neurons activates autophagy and rescues the impaired synaptic plasticity and cognition in Fmr1-KO mice [45]. 

The findings indicate that the mTOR-dependent autophagy is impaired in FXS and activation of autophagy through mTOR inhibition prevents the neuronal deficits in FXS.

Recent studies have reported dysregulation of mTOR-dependent autophagy in other neurodevelopmental disorders including Schaaf-Yang syndrome (SHFYNG) and Koolen-de Vries syndrome (KdVS) [46, 47]. 

SHFYNG is a neurodevelopmental disorder caused by MAGEL2 mutations and the patients with SHFYNG show feeding difficulties, intellectual disability cognitive impairment, and increased prevalence of ASD [48–50]. Schaaf et al. reported that the mTOR activity is increased, accompanied by decreased autophagy flux in MAGEL2 null mice and fibroblasts derived from SHFYNG patients [46]. 

The induced pluripotent stem cell (iPSC)-derived neurons from SHFYNG patients show impaired dendrite formation which can be rescued by treatment with rapamycin [46]. KdVS is a neurodevelopmental disorder caused by mutations with loss-of-function in the KANSL1 gene and patients with KdVS manifest epilepsy, congenital malformations, and developmental delay [51–53]. 

Most recently, Kasri et al. have reported that iPSC-derived neurons from KdVS patients display accumulated autophagosomes at excitatory synapses, resulting in reduced synaptic density and impaired neuronal network activity [47]. 

Mechanistically, they found that in these iPSC-derived neurons, the mTOR activity is enhanced and the lysosome function is decreased, thus preventing the clearance of autophagosome [47]. Taken together, these findings indicate that mTOR-dependent autophagy is disrupted in these neurodevelopmental disorders.

Autophagy controls neurogenesis

The evidence that loss-of-function mutations in essential autophagy genes cause neurodevelopmental disorders demonstrates the crucial role of autophagy in neurodevelopment. What is the mechanism underlying the function of autophagy in controlling neurodevelopment? Autophagy is constitutively active in the development of CNS [54]. 

Through digesting the toxic proteins or aggregates and damaged organelles, autophagy critically regulates neuronal plasticity during neuronal development. Given the growing interest in the role of autophagy in neural proliferation and the maintenance of neuronal stem cells (NSC), here we review the evidence linking autophagy to neurogenesis. 

By using knockout strategies, previous studies have investigated the role of autophagy in embryonic neurogenesis [55]. Jiao et al. have shown a crucial role of autophagy in cortical neurogenesis during early brain development [56]. 

They found that the ATG5 expression increased during cortical development and differentiation [56]. Suppression of ATG5 by using electroporation of short hairpin shRNAs causes reduced neural progenitor cells (NPCs) differentiation, and consequent impaired morphology of cortical neurons [56]. 

Mechanistic investigations indicate that ATG5-mediated autophagy regulates the β-Catenin signaling pathway, which is critical for NPCs proliferation and differentiation in neurodevelopment. 

They showed that autophagy cooperates with β-Catenin to modulate the proliferation and differentiation of cortical NPCs in embryonic neurogenesis during brain development [56]. Furthermore, another study reported that depletion of ATG5 represses astrocyte differentiation in vitro and in the developing mouse cortex, whereas overexpression of ATG5 enhances astrocyte differentiation [57]. 

Additional evidence indicated that through promoting the degradation of SOCS2, ATG5-mediated autophagy activates the JAK2-STAT3 signaling, which regulates the differentiation of astrocytes, while the impaired astrocyte differentiation caused by ATG5 deficiency can be rescued by SOCS2 knockdown [57]. These studies indicate that ATG5-mediated autophagy regulates both neurogenesis and gliogenesis during early brain development.

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