Early infantile neuronal ceroid lipofuscinosis (CLN10 disease) associated with a novel mutation in CTSD

Doccini, Stefano; Sartori, Stefano; Maeser, Stefan; Pezzini, Francesco; Rossato, Sara; Moro, Francesca; Toldo, Irene; Przybylski, Michael; Santorelli, Filippo M.; Simonati, Alessandro

doi:10.1007/s00415-016-8111-6

Cited by 24 publications

(16 citation statements)

References 14 publications

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“…CTSD encodes a palmitoylated lysosomal enzyme (Cathepsin D, CatD), involved in several biological processes (Koch et al, 2013 ; Khalkhali-Ellis and Hendrix, 2014 ). Mutations in CTSD are associated with congenital and infantile-onset NCL (MIM #610127; Siintola et al, 2006 ; Doccini et al, 2016 ). The processing of pro-CatD to mature CatD occurs in the lysosomal compartment, but its maturation is disrupted in the Ppt1 −/− mice, possibly due to the elevated lysosomal pH (Chandra et al, 2015 ; Bagh et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

Pezzini

Bianchi

Benfatto

et al. 2017

Front. Mol. Neurosci.

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CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p.wtCLN1) and five selected CLN1 patients’ mutations. The cellular distribution of wtPPT1 was consistent with regular processing of endogenous protein, partially detected inside Lysosomal Associated Membrane Protein 2 (LAMP2) positive vesicles, while the mutants displayed more diffuse cytoplasmic pattern. Transcriptomic profiling revealed 802 differentially expressed genes (DEGs) in SH-p.wtCLN1 (as compared to empty-vector transfected cells), whereas the number of DEGs detected in the two mutants (p.L222P and p.M57Nfs*45) was significantly lower. Bioinformatic scrutiny linked DEGs with neurite formation and neuronal transmission. Specifically, neuritogenesis and proliferation of neuronal processes were predicted to be hampered in the wtCLN1 overexpressing cell line, and these findings were corroborated by morphological investigations. Palmitoylation survey identified 113 palmitoylated protein-encoding genes in SH-p.wtCLN1, including 25 ones simultaneously assigned to axonal growth and synaptic compartments. A remarkable decrease in the expression of palmitoylated proteins, functionally related to axonal elongation (GAP43, CRMP1 and NEFM) and of the synaptic marker SNAP25, specifically in SH-p.wtCLN1 cells was confirmed by immunoblotting. Subsequent, bioinformatic network survey of DEGs assigned to the synaptic annotations linked 81 DEGs, including 23 ones encoding for palmitoylated proteins. Results obtained in this experimental setting outlined two affected functional modules (connected to the axonal and synaptic compartments), which can be associated with an altered gene dosage of wtCLN1. Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the Ppt1 knockout mice and patients with CLN1 disease.

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Section: Discussionmentioning

confidence: 99%

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

Pezzini

Bianchi

Benfatto

et al. 2017

Front. Mol. Neurosci.

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“…According to the ClinVar Database, 21 mutations have been identified related to CLN10 and affecting the CTSD gene; they include 19 single nucleotide variants, one insertion, and one duplication. Among the 21 mutations, only nine mutations have been confirmed to be pathogenic and linked to the development of CLN10: six missense mutations (p.Phe229Ile, p.Trp383Cys [42], p.Gly149Val, p.Arg399His [124], p.Ser100Phe [125], p.Glu69Lys [126]), a nonsense mutation (c.764dup, p.Tyr255Ter [127]), an insertion (c.268_269insC, p.Gln90fs [128]), and one deletion (p.Phe229del [129]). All different mutations result in neuropathogenesis whose extension is determined by the degree of CTSD gene function loss.…”

Section: Gene Deficiency Biological Effect Referencesmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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“…Human subjects with CLN10 -disease either die prenatally or within a few weeks after birth. Typically, these patients present with microcephaly and seizures and unlike other forms of NCLs they lack the progressive cognitive/motor or visual deficits [153, 154]. Sporadic mutations in the CLN10 gene causing CTSD deficiency in sheep have been reported as congenital ovine NCL [155] and in American bulldogs [156].…”

Section: Introductionmentioning

confidence: 99%

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses

Mukherjee

Appu

Sadhukhan

et al. 2019

Mol Neurodegeneration

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Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called ceroid) and progressive neuron loss. Despite intense studies the normal physiological functions of each of the CLN genes remain poorly understood. Consequently, the development of mechanism-based therapeutic strategies remains challenging. Endolysosomal dysfunction contributes to pathogenesis of virtually all LSDs. Studies within the past decade have drastically changed the notion that the lysosomes are merely the terminal degradative organelles. The emerging new roles of the lysosome include its central role in nutrient-dependent signal transduction regulating metabolism and cellular proliferation or quiescence. In this review, we first provide a brief overview of the endolysosomal and autophagic pathways, lysosomal acidification and endosome-lysosome and autophagosome-lysosome fusions. We emphasize the importance of these processes as their dysregulation leads to pathogenesis of many LSDs including the NCLs. We also describe what is currently known about each of the 13 CLN genes and their products and how understanding the emerging new roles of the lysosome may clarify the underlying pathogenic mechanisms of the NCLs. Finally, we discuss the current and emerging therapeutic strategies for various NCLs.

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Early infantile neuronal ceroid lipofuscinosis (CLN10 disease) associated with a novel mutation in CTSD

Cited by 24 publications

References 14 publications

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses

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