Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

Salgado-Polo, Fernando; Veen, Michiel van; Broek, Bram van den; Jalink, Kees; Leyton-Puig, Daniela; Perrakis, Anastassis; Matas-Rico, Elisa

doi:10.1242/jcs.235044

Cited by 13 publications

(7 citation statements)

References 40 publications

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“…In uninfected CAD and SH-SY5Y cells, both Rab5 and Rab11 concentrate at one perinuclear region (Fig. 7A, D, G, and K), consistent with previous observations (28,41). This concentration of membranes is dependent on the microtubule network (Fig.…”

Section: Resultssupporting

confidence: 91%

Herpes Simplex Virus Organizes Cytoplasmic Membranes To Form a Viral Assembly Center in Neuronal Cells

White

Kawano

Harata

et al. 2020

J Virol

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Herpes simplex virus (HSV) is a neuroinvasive virus that has been used as a model organism for studying common properties of all herpesviruses. HSV induces host organelle rearrangement and forms multiple, dispersed assembly compartments in epithelial cells, which complicates the study of HSV assembly. In this study, we show that HSV forms a visually distinct unitary cytoplasmic viral assembly center (cVAC) in both cancerous and primary neuronal cells that concentrates viral structural proteins and is a major site of capsid envelopment. The HSV cVAC also concentrates host membranes that are important for viral assembly, such as Golgi- and recycling endosome-derived membranes. Lastly, we show that HSV cVAC formation and/or maintenance depends on an intact microtubule network and a viral tegument protein, pUL51. Our observations suggest that the neuronal cVAC is a uniquely useful model to study common herpesvirus assembly pathways, and cell-specific pathways for membrane reorganization. Importance Herpesvirus particles are complex and contain many different proteins that must come together in an organized and coordinated fashion. Many viruses solve this coordination problem by creating a specialized assembly factory in the host cell, and the formation of such factories provides a promising target for interfering with virus production. Herpes simplex virus 1 (HSV-1) infects several types of cells, including neurons, but has not previously been shown to form such an organized factory in the non-neuronal cells in which its assembly has been best studied. Here we show that HSV-1 forms an organized assembly factory in neuronal cells, and we identify some of the viral and host cell factors that are important for its formation.

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Section: Resultssupporting

confidence: 91%

Herpes Simplex Virus Organizes Cytoplasmic Membranes To Form a Viral Assembly Center in Neuronal Cells

White

Kawano

Harata

et al. 2020

J Virol

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“…Our studies showed that BACE expression was not affected by GDE2 and RECK expression. GDE2 and RECK function on the plasma membrane and not endosomes (21,29,(40)(41)(42), and putative activation functions of RECK on aspartyl proteases such as BACE have not been reported. Accordingly, potential effects of GDE2-RECK on BACE are likely to be indirect.…”

Section: Discussionmentioning

confidence: 99%

“…S4, table S1, and data file S1). Because GDE2 function requires expression on the cell surface (26,29), these observations suggest that GDE2 trafficking and function are disrupted in neurons of patients with AD.…”

Section: Of 14mentioning

confidence: 99%

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

Nakamura

Choi

et al. 2021

Sci. Transl. Med.

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A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer’s disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)–anchored inhibitor of ADAM10. In AD, membrane-tethered RECK is highly elevated and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. These studies identify GDE2 control of RECK surface activity as essential for ADAM10 α-secretase function and physiological APP processing. Moreover, our results suggest the involvement of the GDE2-RECK-ADAM10 pathway in AD pathophysiology and highlight RECK as a potential target for therapeutic development.

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“…In contrast to control patients, we find that in motor cortex of patients with ALS, hGDE2 is no longer expressed on the cell surface but instead aberrantly accumulates within cells. Structure-function studies in heterologous cells have shown that surface expression of GDE2 is critical for its GPI-anchor cleavage function [36]. Accordingly, intracellular accumulation of hGDE2 in ALS patient samples is suggestive of a failure of GDE2 enzymatic function in ALS.…”

Section: Discussionmentioning

confidence: 99%

The distribution and function of GDE2, a regulator of spinal motor neuron survival, are disrupted in Amyotrophic Lateral Sclerosis

Westerhaus

Joseph

Meyers

et al. 2022

acta neuropathol commun

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the viability of upper and lower motor neurons. Current options for treatment are limited, necessitating deeper understanding of the mechanisms underlying ALS pathogenesis. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that acts on the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. GDE2 is required for the survival of spinal motor neurons but whether GDE2 neuroprotective activity is disrupted in ALS is not known. We utilized a combination of mouse models and patient post-mortem samples to evaluate GDE2 functionality in ALS. Haplogenetic reduction of GDE2 exacerbated motor neuron degeneration and loss in SOD1G93A mice but not in control SOD1WT transgenic animals, indicating that GDE2 neuroprotective function is diminished in the context of SOD1G93A. In tissue samples from patients with ALS, total levels of GDE2 protein were equivalent to healthy controls; however, membrane levels of GDE2 were substantially reduced. Indeed, GDE2 was found to aberrantly accumulate in intracellular compartments of ALS motor cortex, consistent with a disruption of GDE2 function at the cell surface. Supporting the impairment of GDE2 activity in ALS, tandem-mass-tag mass spectrometry revealed a pronounced reduction of GPI-anchored proteins released into the CSF of patients with ALS compared with control patients. Taken together, this study provides cellular and biochemical evidence that GDE2 distribution and activity is disrupted in ALS, supporting the notion that the failure of GDE2-dependent neuroprotective pathways contributes to neurodegeneration and motor neuron loss in disease. These observations highlight the dysregulation of GPI-anchored protein pathways as candidate mediators of disease onset and progression and accordingly, provide new insight into the mechanisms underlying ALS pathogenesis.

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Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

Cited by 13 publications

References 40 publications

Herpes Simplex Virus Organizes Cytoplasmic Membranes To Form a Viral Assembly Center in Neuronal Cells

Herpes Simplex Virus Organizes Cytoplasmic Membranes To Form a Viral Assembly Center in Neuronal Cells

GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein

The distribution and function of GDE2, a regulator of spinal motor neuron survival, are disrupted in Amyotrophic Lateral Sclerosis

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