N-glycosylation requirements in neuromuscular synaptogenesis

Parkinson, William; Dear, Mary Lynn; Rushton, Emma; Broadie, Kendal

doi:10.1242/dev.099192

Cited by 34 publications

(45 citation statements)

References 84 publications

(117 reference statements)

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“…In Drosophila , N-glycosylation is vital for synaptogenesis, where the absence of hybrid and complex chains (due to MGAT1 deficiency) causes an imbalance in the bidirectional trans-synaptic signaling due to an imbalance in the lectin localization within the synaptomatrix (Parkinson et al 2013). …”

Section: Basis Of Clinical Presentationsmentioning

confidence: 99%

Neurological Aspects of Human Glycosylation Disorders

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Eklund²,

et al. 2015

Annu. Rev. Neurosci.

202

170

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This review will present principles of glycosylation, describe the relevant glycosylation pathways and their related disorders, and highlight some of the neurological aspects and issues that continue to challenge researchers. Over 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delay/intellectual disability, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Between these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of mis-glycosylated products afflicting a myriad of processes including cell signaling, cell-cell interaction and cell migration. This vast complexity in glycan composition and function, along with limited analytic tools has impeded the identification of key glycosylated molecules that cause pathologies, and to date few critical target proteins have been pinpointed.

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Section: Basis Of Clinical Presentationsmentioning

confidence: 99%

Neurological Aspects of Human Glycosylation Disorders

Freeze

Eklund²,

et al. 2015

Annu. Rev. Neurosci.

202

170

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“…UDP-galactose substrate deficiency is one of the proposed contributing pathophysiological mechanisms (Gibson et al 1995;Lai et al 2003;Parkinson et al 2013;Jumbo-Lucioni et al 2014).…”

Section: Serum Igg N-glycosylation Abnormalities In Galactosaemiamentioning

confidence: 99%

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

et al. 2016

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Classical galactosaemia is a rare disorder of carbohydrate metabolism caused by galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12). The disease is life threatening if left untreated in neonates and the only available treatment option is a long-term galactose restricted diet. While this is lifesaving in the neonate, complications persist in treated individuals, and the cause of these, despite early initiation of treatment, and shared GALT genotypes remain poorly understood. Systemic abnormal glycosylation has been proposed to contribute substantially to the ongoing pathophysiology. The gross N-glycosylation assembly defects observed in the untreated neonate correct over time with treatment. However, N-glycosylation processing defects persist in treated children and adults.Congenital disorders of glycosylation (CDG) are a large group of over 100 inherited disorders affecting largely N-and O-glycosylation.In this review, we compare the clinical features observed in galactosaemia with a number of predominant CDG conditions.We also summarize the N-glycosylation abnormalities, which we have described in galactosaemia adult and paediatric patients, using an automated high-throughput HILIC-UPLC analysis of galactose incorporation into serum IgG with analysis of the corresponding N-glycan gene expression patterns and the affected pathways.

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“…Extracellular regulation of trans-synaptic signaling is important for modulating both structural and functional synaptic development Parkinson et al, 2013;Dani et al, 2014). Both Mmp classes reside within the synaptomatrix, where they are perfectly positioned to participate in this mechanism and the LOF phenotypes are consistent with increased Wnt trans-synaptic signaling at the NMJ.…”

Section: Mmp1 and Mmp2 Restrict Wnt Trans-synaptic Signalingmentioning

confidence: 99%

“…See supplementary Materials and Methods for full sequences. SDS-PAGE western blots of neuromusculature and CNS were performed as previously described (Parkinson et al, 2013). For further details of methods and antibodies used for blotting, see supplementary Materials and Methods.…”

Section: Antibody Production and Western Blot Analysesmentioning

confidence: 99%

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

et al. 2015

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Synaptogenesis requires orchestrated intercellular communication between synaptic partners, with trans-synaptic signals necessarily traversing the extracellular synaptomatrix separating presynaptic and postsynaptic cells. Extracellular matrix metalloproteinases (Mmps) regulated by secreted tissue inhibitors of metalloproteinases (Timps), cleave secreted and membrane-associated targets to sculpt the extracellular environment and modulate intercellular signaling. Here, we test the roles of Mmp at the neuromuscular junction (NMJ) model synapse in the reductionist Drosophila system, which contains just two Mmps (secreted Mmp1 and GPI-anchored Mmp2) and one secreted Timp. We found that all three matrix metalloproteome components co-dependently localize in the synaptomatrix and show that both Mmp1 and Mmp2 independently restrict synapse morphogenesis and functional differentiation. Surprisingly, either dual knockdown or simultaneous inhibition of the two Mmp classes together restores normal synapse development, identifying a reciprocal suppression mechanism. The two Mmp classes coregulate a Wnt trans-synaptic signaling pathway modulating structural and functional synaptogenesis, including the GPIanchored heparan sulfate proteoglycan (HSPG) Wnt co-receptor Dally-like protein (Dlp), cognate receptor Frizzled-2 (Frz2) and Wingless (Wg) ligand. Loss of either Mmp1 or Mmp2 reciprocally misregulates Dlp at the synapse, with normal signaling restored by coremoval of both Mmp classes. Correcting Wnt co-receptor Dlp levels in both Mmp mutants prevents structural and functional synaptogenic defects. Taken together, these results identify an Mmp mechanism that fine-tunes HSPG co-receptor function to modulate Wnt signaling to coordinate synapse structural and functional development.

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N-glycosylation requirements in neuromuscular synaptogenesis

Cited by 34 publications

References 84 publications

Neurological Aspects of Human Glycosylation Disorders

Neurological Aspects of Human Glycosylation Disorders

Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

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