Towards understanding the neuronal ceroid lipofuscinoses

doi:10.1016/j.braindev.2008.12.008

Brain and Development

Volume 31, Issue 7, August 2009, Pages 499-502

https://doi.org/10.1016/j.braindev.2008.12.008 Get rights and content

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a group of genetic progressive brain diseases of children and young adults, characterized by a decline of mental and other capacities, epilepsy, and visual loss through retinal degeneration. The common pathology of NCLs is that of a storage disorder with accumulation of an autofluorescent material, ceroid lipofuscin, in combination with the degeneration of neuronal cells. At least 10 genetically distinct NCLs, designated CLN1 to CLN10, are presently known. Several NCLs exhibit a widely variable clinical picture, depending on the severity of the individual mutation. Some NCLs are not particularly rare. With increasing awareness of these disorders and better diagnostic techniques available, the number of recognized patients is rising. This overview briefly summarizes recent developments (or quotes corresponding literature) that are important to understand, diagnose, and manage patients suffering from one of these incurable disorders.

Introduction

The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of genetic degenerative brain diseases characterized by a progressive decline of mental and motor capacities, epilepsy, and visual loss through retinal degeneration. NCLs can affect humans from birth to young adulthood. Some representatives of this group are not extremely rare. With increasing awareness of these disorders and better diagnostic techniques, the number of recognized patients is rising. The number of established NCL disease entities has also risen to a number of presently at least 10 different disorders (Table 1). While the NCLs are now classified according to the designation of the mutated gene, Table 1 lists the single disorders in order of the age at which they typically become manifest. It must be noted, however, that genetic variants with “mild” mutations can have a significantly later onset than their “classical” forms.

For physicians as for basic scientists, it is practical to look upon the different types of NCL as a group of disorders as they have many things in common. Clinically, they are progressive neurological diseases characterized almost always by a combination of retinopathy, dementia, and epilepsy. Their pathology is that of a storage disorder with accumulation of a material termed ceroid lipofuscin in combination with the degeneration of neuronal cells. The purpose of this short overview is not to review the NCLs, for which comprehensive accounts exist [1], [2], but to give a report on progress in the NCLs that is of importance when confronted with patients suspected or proven to suffer from such a disease. Readers more interested in basic mechanisms are referred to recent reviews [3].

In the following, the single NCLs are dealt with in the order of their genetic designation CLN1 to CLN10.

Section snippets

The single NCL disorders

CLN1. The classical infantile NCL (INCL) manifests itself in the second half of the first year of life and progresses dramatically with seizures, mental decay, loss of vision, and brain atrophy. Some mutations cause manifestation at any age, including adulthood [4]. The underlying defect is the lack of activity of the lysosomal palmitoylthioesterase 1 (PPT1) which can be used for diagnosis. As the enzyme cleaves fatty acid thioesters in plasma membranes, it was suggested that the drug

Diagnostic strategy in suspected NCL disorders

An economical approach to diagnosis of a suspected NCL starts from the type of clinical manifestation (see Fig. 2). In a neonate with microcephaly and convulsions, CLN10 with cathepsin D deficiency is a possibility. The enzyme deficiency is detected best in cultivated skin fibroblasts. In young children with otherwise unexplained epilepsy and developmental standstill, CLN2 and CLN3 are the most frequent diagnoses which are detected by the respective enzyme deficiencies leukocytes, fibroblasts,

Treatment of NCLs

NCLs are incurable. Long-term palliative treatment that takes into consideration specific aspects of the particular type of NCL in question, is of great importance to obtain the best attainable quality of life [2]. Some experimental therapeutic trials aiming at the prevention of neurological progression have been mentioned above. The theoretical chances of enzyme replacement, gene therapy, cell-mediated therapy and pharmacological treatments in NCLs have been reviewed [20]. As the effects of

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The conserved cellular roles of CLN proteins: Novel insights from Dictyostelium discoideum
2023, European Journal of Cell Biology
The neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease, are a group of fatal neurodegenerative disorders that primarily affect children. The etiology of Batten disease is linked to mutations in 13 genes that encode distinct CLN proteins, whose functions have yet to be fully elucidated. The social amoeba Dictyostelium discoideum has been adopted as an efficient and powerful model system for studying the diverse cellular roles of CLN proteins. The genome of D. discoideum encodes several homologs of human CLN proteins, and a growing body of literature supports the conserved roles and networking of CLN proteins in D. discoideum and humans. In humans, CLN proteins have diverse cellular roles related to autophagy, signal transduction, lipid homeostasis, lysosomal ion homeostasis, and intracellular trafficking. Recent work also indicates that CLN proteins play an important role in protein secretion. Remarkably, many of these findings have found parallels in studies with D. discoideum. Accordingly, this review will highlight the translatable value of novel work with D. discoideum in the field of NCL research and propose further avenues of research using this biomedical model organism for studying the NCLs.
Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme
2022, Molecular Genetics and Metabolism Reports
Neuronal ceroid lipofuscinosis type 1(CLN1 disease) is a rare autosomal recessive lysosomal storage disease caused by genetic defects of palmitoyl protein thioesterase-1(PPT1), leading to accumulation of lipofuscin granules in brain and progressive neurodegeneration. Psychomotor regression, seizures, loss of vision, and movement disorder begin in infancy and result in early death. Currently, no disease-modifying therapy is available.
We report a 68-month-old boy with CLN1 treated on a compassionate use basis weekly for 26 months with a PPT1 enzyme fused to an anti-insulin receptor antibody (AGT-194), thereby enabling penetration of the blood-brain barrier (BBB). During treatment, no side effects were observed, while seizure frequency decreased, life quality improved, and the boy's general condition remained stable.
This case documents for the first time that treatment of CLN1 is principally feasible by an intravenous BBB penetrating enzyme replacement therapy using PPT1 fused with the human insulin receptor. Monitoring of side effects raised no unacceptable or unexpected safety concerns.Observed improvement of life quality related to ameliorated epilepsy control raises hope that further robust clinical trials including patients in earlier stages of disease will show positive results.
Blood-brain barrier delivery for lysosomal storage disorders with IgG-lysosomal enzyme fusion proteins
2022, Advanced Drug Delivery Reviews
The majority of lysosomal storage diseases affect the brain. Treatment of the brain with intravenous enzyme replacement therapy is not successful, because the recombinant lysosomal enzymes do not cross the blood–brain barrier (BBB). Biologic drugs, including lysosomal enzymes, can be re-engineered for BBB delivery as IgG-enzyme fusion proteins. The IgG domain of the fusion protein is a monoclonal antibody directed against an endogenous receptor-mediated transporter at the BBB, such as the insulin receptor or the transferrin receptor. This receptor transports the IgG across the BBB, in parallel with the endogenous receptor ligand, and the IgG acts as a molecular Trojan horse to ferry into brain the lysosomal enzyme genetically fused to the IgG. The IgG-enzyme fusion protein is bi-functional and retains both high affinity binding for the BBB receptor, and high lysosomal enzyme activity. IgG-lysosomal enzymes are presently in clinical trials for treatment of the brain in Mucopolysaccharidosis.
Generation of pathogenic TPP1 mutations in human stem cells as a model for neuronal ceroid lipofuscinosis type 2 disease
2021, Stem Cell Research
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive neurodegenerative disorder generally with onset at 2 to 4 years of age and characterized by seizures, loss of vision, progressive motor and mental decline, and premature death. CLN2 disease is caused by loss-of-function mutations in the tripeptidyl peptidase 1 (TPP1) gene leading to deficiency in TPP1 enzyme activity. Approximately 60% of patients have one of two pathogenic variants (c.509-1G > C or c.622C > T [p.(Arg208*)]). In order to generate a human stem cell model of CLN2 disease, we used CRISPR/Cas9-mediated knock-in technology to introduce these mutations in a homozygous state into H9 human embryonic stem cells. Heterozygous lines of the c.622C > T (p.(Arg208*)) mutation were also generated, which included a heterozygous mutant with a wild-type allele and different compound heterozygous coding mutants resulting from indels on one allele. We describe the methodology that led to the generation of the lines and provide data on the initial validation and characterization of these CLN2 disease models. Notably, both mutant lines (c.509-1G > C and c.622C > T [p.(Arg208*)]) in the homozygous state were shown to have reduced or absent protein, respectively, and deficiency of TPP1 enzyme activity. These models, which we have made available for wide-spread sharing, will be useful for future studies of molecular and cellular mechanisms underlying CLN2 disease and for therapeutic development.
Pathomechanisms in the neuronal ceroid lipofuscinoses
2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
These include the pathognomic accumulation of autofluorescent storage material (AFSM), dysregulated autophagy as well as significant and progressive glial activation and neuronal death within the nervous system [6–8]. It is important to note that since the NCLs arise from distinct monogenetic mutations, each form may have unique pathomechanisms that affect the endo-lysosomal system that can result in these phenotypes [5,6,9]. Nevertheless, these diseases ultimately end in broadly similar pathological appearances.
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs), traditionally grouped together based on shared clinical symptoms. The recent emergence of new forms of NCL along with an improved understanding of endo-lysosomal system function have necessitated the reassessment of their classification and pathogenesis. Novel clinical findings, as well as observations in various animal models of NCL, have revealed significant pathological changes in regions outside the brain, as well as progression of disease along connected anatomical pathways. The characterization of animal models of NCLs has not only highlighted the vulnerability of certain neuron populations but has also revealed glial cells to be adversely affected and actively contribute to disease progression. While the lysosome has been thought of as being the ‘waste-disposal’ unit of the cell, recent evidence of the endo-lysosomal system playing a crucial role in nutrient sensing and cellular homeostasis have shown that NCL mutations have far-ranging effects on cellular functions including autophagy and synaptic dysfunction. The discovery of the machinery controlling endo-lysosomal function via transcription factor EB (TFEB) and mTORC1, have also shed light on potential mechanisms by which NCL mutations may exert their effect. While the NCLs share many common down-stream pathologies, there is a growing body of evidence for unique pathogenic pathways in each form. In light of the rapid advances in therapeutic strategies for the NCLs and LSDs, these new lessons learnt about unique NCL pathomechanisms will be key for informing the targeting, timing and strategies for future treatments.
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The aggregation of nanoparticle colloidal dispersions in complex biological environments changes the nanoparticle properties, such as size and surface area, thus affecting the interaction of nanoparticles at the interface with cellular components and systems. We investigated the effect of nanoparticle aggregation on autophagy, the main catabolic pathway that mediates degradation of nanosized materials and that is activated in response to internalization of foreign nanosized materials. We used carboxylated polystyrene nanoparticles (100 nm) and altered the nanoparticle aggregation behavior through addition of a multidomain peptide, thus generating a set of nanoparticle-peptide mixtures with variable aggregation properties. Specifically, modulating the peptide concentration resulted in nanoparticle-peptide mixtures that are well dispersed extracellularly but aggregate upon cellular internalization. We monitored the effect of internalization of nanoparticle-peptide mixtures on a comprehensive set of markers of the autophagy pathway, ranging from transcriptional regulation to clearance of autophagic substrates. The nanoparticle-peptide mixtures were found to activate the transcription factor EB, a master regulator of autophagy and lysosomal biogenesis. We also found that intracellular aggregation of nanoparticle colloidal dispersions causes blockage of autophagic flux. This study provides important insights on the effect of the aggregation properties of nanoparticles on cells and, particularly, on the main homeostatic pathway activated in response to nanoparticle internalization. These results also point to the need to control the colloidal stability of nanoparticle systems for a variety of biomedical applications.

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Review articleTowards understanding the neuronal ceroid lipofuscinoses

Abstract

Introduction

Section snippets

The single NCL disorders

Diagnostic strategy in suspected NCL disorders

Treatment of NCLs

Mol Ther

Am J Hum Genet

Pediatr Neurol

J Biol Chem

Am J Hum Genet

The Neuronal Ceroid Lipofuscinoses

Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1

Neurology

Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: implications for treatment of infantile neuronal ceroid lipofuscinosis

J Inherit Metab Dis

Review article
Towards understanding the neuronal ceroid lipofuscinoses