Monocytes and macrophages as biomarkers for the diagnosis of megalencephalic leukoencephalopathy with subcortical cysts

Petrini, Stefania; Minnone, Gaetana; Coccetti, Marianna; Frank, Claudio; Aiello, Chiara; Cutarelli, Alessandro; Ambrosini, Elena; Lanciotti, Angela; Brignone, Maria Stefania; D’Oria, Valentina; Strippoli, Raffaele; Benedetti, Fabrizio; Bertini, Enrico; Bracci-Laudiero, Luisa

doi:10.1016/j.mcn.2013.07.001

Cited by 18 publications

(27 citation statements)

References 51 publications

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“…S3a,d). In macrophages from two MLC patients, each carrying a different MLC1 mutation (see Materials and methods), MLC1 immunoreactivity was almost undetectable in the plasma membrane, as previously reported (Petrini et al, 2013), and showed reduced colocalization with cytoplasmic organelle markers, particularly with Rab11 (Figs. S3b,c,e,f).…”

Section: Resultssupporting

confidence: 80%

Megalencephalic leukoencephalopathy with subcortical cysts protein-1 modulates endosomal pH and protein trafficking in astrocytes: Relevance to MLC disease pathogenesis

Brignone

Lanciotti

Visentin

et al. 2014

Neurobiology of Disease

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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by mutations in the gene encoding MLC1, a membrane protein mainly expressed in astrocytes in the central nervous system. Although MLC1 function is unknown, evidence is emerging that it may regulate ion fluxes. Using biochemical and proteomic approaches to identify MLC1 interactors and elucidate MLC1 function we found that MLC1 interacts with the vacuolar ATPase (V-ATPase), the proton pump that regulates endosomal acidity. Because we previously showed that in intracellular organelles MLC1 directly binds Na, K-ATPase, which controls endosomal pH, we studied MLC1 endosomal localization and trafficking and MLC1 effects on endosomal acidity and function using human astrocytoma cells overexpressing wild-type (WT) MLC1 or MLC1 carrying pathological mutations. We found that WT MLC1 is abundantly expressed in early (EEA1+, Rab5+) and recycling (Rab11+) endosomes and uses the latter compartment to traffic to the plasma membrane during hyposmotic stress. We also showed that WT MLC1 limits early endosomal acidification and influences protein trafficking in astrocytoma cells by stimulating protein recycling, as revealed by FITC-dextran measurement of endosomal pH and transferrin protein recycling assay, respectively. WT MLC1 also favors recycling to the plasma-membrane of the TRPV4 cation channel which cooperates with MLC1 to activate calcium influx in astrocytes during hyposmotic stress. Although MLC disease-causing mutations differentially affect MLC1 localization and trafficking, all the mutated proteins fail to influence endosomal pH and protein recycling. This study demonstrates that MLC1 modulates endosomal pH and protein trafficking suggesting that alteration of these processes contributes to MLC pathogenesis.

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Section: Resultssupporting

confidence: 80%

Megalencephalic leukoencephalopathy with subcortical cysts protein-1 modulates endosomal pH and protein trafficking in astrocytes: Relevance to MLC disease pathogenesis

Brignone

Lanciotti

Visentin

et al. 2014

Neurobiology of Disease

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“…MLC1 expression is enriched in astrocytic processes contacting capillaries and meninges and in cerebellar Bergmann glia 15, 16, 17, 18. GlialCAM shows a similar expression pattern, and is also expressed in oligodendrocytes 17, 19.…”

Section: Introductionmentioning

confidence: 97%

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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ObjectiveMegalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies.MethodsWe investigated the consequences of loss of GlialCAM in Glialcam‐null mice and compared GlialCAM developmental expression in mice and men.Results Glialcam‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam‐null astrocytes showed abolished expression of MLC1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC1‐interacting proteins and the volume regulated anion channel LRRC8A was unchanged. In mice, GlialCAM expression increased until 3 weeks and then stabilized. In humans, GlialCAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years.Interpretation Glialcam‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC. GlialCAM expression affects expression of MLC1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.

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“…14,15 Depletion of MLC1 in lymphoblasts and astrocytes reduces volumeregulated anion channel currents (VRAC) and slows the regulatory volume decrease after cell swelling. 14,15 Depletion of MLC1 in lymphoblasts and astrocytes reduces volumeregulated anion channel currents (VRAC) and slows the regulatory volume decrease after cell swelling.…”

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confidence: 99%

“…In humans, MLC1 is exclusively expressed in cells of astroglial lineage and leukocytes. 14,15 Depletion of MLC1 in lymphoblasts and astrocytes reduces volumeregulated anion channel currents (VRAC) and slows the regulatory volume decrease after cell swelling. 16 Despite emerging insights into the role of MLC1 in brain ionwater homeostasis, the pathomechanisms underlying MLC are still poorly understood.…”

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confidence: 99%

Mice with megalencephalic leukoencephalopathy with cysts: A developmental angle

Dubey

Bugiani

Ridder

et al. 2014

Annals of Neurology

131

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Mlc1-null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC-2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC.

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Monocytes and macrophages as biomarkers for the diagnosis of megalencephalic leukoencephalopathy with subcortical cysts

Cited by 18 publications

References 51 publications

Megalencephalic leukoencephalopathy with subcortical cysts protein-1 modulates endosomal pH and protein trafficking in astrocytes: Relevance to MLC disease pathogenesis

Megalencephalic leukoencephalopathy with subcortical cysts protein-1 modulates endosomal pH and protein trafficking in astrocytes: Relevance to MLC disease pathogenesis

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Mice with megalencephalic leukoencephalopathy with cysts: A developmental angle

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