Reactivation of Lysosomal Ca<sup>2+</sup>Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells

Zou, Jianlong; Hu, Bo; Arpag, Sezgi; Yan, Qing; Hamilton, Audra; Zeng, Yuan; Vanoye, Carlos G.; Li, Jun

doi:10.1523/jneurosci.4442-14.2015

Cited by 46 publications

(60 citation statements)

References 46 publications

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“…Therefore, PI3,5P 2 deficiency in Fig4 −/− cells would deactivate the TRPML-1 channel and impair lysosomal membrane trafficking. Indeed, our studies have shown increased intralysosomal Ca 2+ and impaired lysosomal fission in Fig4 −/− cells, including myelinating Schwann cells 11 . Lysosomal membrane trafficking has been suggested to be important for myelination 12,13 .…”

Section: Introductionmentioning

confidence: 59%

“…Our previous study has shown that abnormal lysosomal storage in FIG4 deficient mouse fibroblasts was mainly caused by a lysosomal fission defect while lysosomal fusion was normal 11 . We verified this mechanism in five patients with CMT4J.…”

Section: Resultsmentioning

confidence: 96%

“…One potential mechanism to be tested in the future is that axons or macrophages with FIG4 deficiency may elevate Ca 2+ levels further or trigger more Ca 2+ release from lysosomes in Fig4 −/− Schwann cells. Because Ca 2+ is already increased in Fig4 −/− Schwann cells 11 , a further increase of cytosolic Ca 2+ level likely initiates a cascade of events leading to demyelination 39 . In line with this idea, axonal damage has been shown to increase intracellular Ca 2+ level in myelin 41 .…”

Section: Discussionmentioning

confidence: 99%

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Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

Mccollum

Ravi

et al. 2018

Annals of Neurology

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Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca . Injection of a Ca chelator into Fig4 mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. Ann Neurol 2018;83:756-770.

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Section: Introductionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

Mccollum

Ravi

et al. 2018

Annals of Neurology

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“…Deficiency of PI(3,5)P 2 results in enlarged endolysosomal vacuoles, possibly generated by osmotic swelling due to impaired activation of the lysosomal cation channels TRPML1 (MIM: 605248), TPCN1 (MIM: 609666), and TPCN2 (MIM: 612163). [10][11][12][13][14] Neurons are particularly sensitive to reduced abundance of PI(3,5)P 2 . 15 Mutations of FIG4 result in recessive neurological disorders, including the peripheral neuropathy Charcot-Marie-Tooth type 4J (MIM: 611228), the multisystem disorder Yunis-Varón syndrome (MIM: 216340), and polymicrogyria with seizures and psychiatric co-morbidities (MIM: 612691).…”

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confidence: 99%

Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Lenk

Sztefko

Dębska–Vielhaber

et al. 2016

The American Journal of Human Genetics

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In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14.

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“…What appears to be a common observation is that TRPML1 plays a role in metal ion homeostasis [21, 28, 31, 64], membrane trafficking [21, 41], and exocytosis of intracellular contents [66, 88] via the endosomal-lysosomal pathway. Recently, the forced induction of TRPML1 channel activity through an agonist or synthetic ligand (ML1-SA) has been shown to rescue phenotypes of various diseased models of Charcot-Marie-Tooth disease Type 4J and human immunodeficiency virus-induced dementia [6, 118]. Thus, the ability of TRPML1 to rescue disease phenotypes involving lysosomes add to a growing evidence of its importance in normal lysosomal physiology.…”

Section: Introductionmentioning

confidence: 99%

The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

Cuajungco

Silva

Habibi

et al. 2015

Pflugers Arch - Eur J Physiol

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The discovery of the TRPML subfamily of ion channels has created an exciting niche in the fields of membrane trafficking, signal transduction, autophagy, and metal homeostasis. The TRPML protein subfamily consist three members, TRPML1, -2, and -3, which are encoded by MCOLN1, -2, and -3 genes, respectively. They are non-selective cation channels with six predicted transmembrane domains, and intracellular amino- and carboxyl-terminus regions. They localize to the plasma membrane, endosomes, and lysosomes of cells. TRPML1 is associated with the human lysosomal storage disease known as Mucolipidosis type IV (MLIV), but TRPML2 and TRPML3 have not been linked with a human disease. Although TRPML1 is expressed in many tissues, TRPML3 is expressed in a varied but limited set of tissues, while TRPML2 has a more limited expression pattern where it is mostly detected in lymphoid and myeloid tissues. This review focuses on TRPML2 because it appears to play an important, yet unrecognized role in the immune system. While the evidence has been mostly indirect, we present and discuss relevant data that strengthen the connection of TRPML2 with cellular immunity. We also discuss the functional redundancy between the TRPML proteins, and how such features could be exploited as a potential therapeutic strategy for MLIV disease. We present evidence that TRPML2 expression may complement certain phenotypic alterations in MLIV cells, and briefly examine the challenges of functional complementation. In conclusion, the function of TRPML2 still remains obscure, but emerging data show that it may serve a critical role in immune cell development and inflammatory responses.

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Reactivation of Lysosomal Ca²⁺Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells

Abstract: Loss of function of FIG4 leads to

Cited by 46 publications

References 46 publications

Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

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Reactivation of Lysosomal Ca2+Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells

Abstract: Loss of function of FIG4 leads to

Cited by 46 publications

References 46 publications

Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

Myelin abnormality in Charcot–Marie–Tooth type 4J recapitulates features of acquired demyelination

Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

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Reactivation of Lysosomal Ca²⁺Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells