Pathomechanisms in the neuronal ceroid lipofuscinoses

Nelvagal, Hemanth R.; Lange, Jenny; Takahashi, Keigo; Tarczyluk-Wells, Marta; Cooper, Jonathan D.

doi:10.1016/j.bbadis.2019.165570

Cited by 56 publications

(87 citation statements)

References 177 publications

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“…Finally, the broadly similar clinical and pathological profiles of the different NCL subtypes suggest that common disease mechanisms may be involved, which has been the focus of this review. However, a growing body of evidence also suggests that distinct mechanisms may be implicated in some forms of NCL, which is not surprising given the diversity of processes affected by mutations in NCL genes and the emerging differences in the nature and timing of pathology for the different subtypes [123]. Therefore, future work that explores both these avenues will be necessary to broaden our understanding of the cellular and molecular mechanisms underlying the NCLs.…”

Section: Alternate Perspectives and Considerationsmentioning

confidence: 99%

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Huber

2020

J Biomed Sci

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The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, belong to a family of neurological disorders that cause blindness, seizures, loss of motor function and cognitive ability, and premature death. There are 13 different subtypes of NCL that are associated with mutations in 13 genetically distinct genes (CLN1-CLN8, CLN10-CLN14). Similar clinical and pathological profiles of the different NCL subtypes suggest that common disease mechanisms may be involved. As a result, there have been many efforts to determine how NCL proteins are connected at the cellular level. A main driving force for NCL research has been the utilization of mammalian and non-mammalian cellular models to study the mechanisms underlying the disease. One non-mammalian model that has provided significant insight into NCL protein function is the social amoeba Dictyostelium discoideum. Accumulated data from Dictyostelium and mammalian cells show that NCL proteins display similar localizations, have common binding partners, and regulate the expression and activities of one another. In addition, genetic models of NCL display similar phenotypes. This review integrates findings from Dictyostelium and mammalian models of NCL to highlight our understanding of the molecular networking of NCL proteins. The goal here is to help set the stage for future work to reveal the cellular mechanisms underlying the NCLs.

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Section: Alternate Perspectives and Considerationsmentioning

confidence: 99%

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Huber

2020

J Biomed Sci

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“…[13,43,119,121,122] Neuronal ceroid lipofuscinosis 10 #610127 CTSD Impaired lysosomal degradation and aberrant autophagy. [42,43,130,131] Neuronal ceroid lipofuscinosis 13 #615362 CTSF Impaired lysosomal degradation and aberrant autophagy. Pycnodysostosis #265800 CTSK Impaired osteoclast-mediated bone resorption.…”

Section: Gene Deficiency Biological Effect Referencesmentioning

confidence: 99%

“…It is not yet clear how CTSD deficiency causes neuropathies; however, experimental evidence suggests defective autophagy might be in part responsible, as CTSD is essential in degrading cellular components during macroautophagy [130]. Several papers have demonstrated a contribution of glial dysfunction and the involvement of various brain regions in the pathogenesis of NCLs [131]. A recent study has revealed a previously unrecognized role for CTSD in selectively modulating inhibitory synaptic vesicle trafficking and synaptic transmission, showing mechanistic evidence that GABAergic presynaptic endosomal dysfunction might account for the synaptic pathology observed in CTSD deficiency-related NCL diseases [132].…”

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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“…The onset of loss of vision progressing to blindness, regression in cognitive and motor abilities, and epileptic abnormalities in early teen-age might underly the change into NCLs. The onset of such symptoms varies in accordance to the type of NCL in every individual [ 16 ]. CLN5 disease was originally identified as a rare variant of NCLs restricted to Finnish and other Northern European populations [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis

Azad

Efthymiou

Sultan³

et al. 2020

Journal of the Neurological Sciences

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Background Neuronal ceroid lipofuscinosis (NCL) is a hereditary lysosomal storage disease with progressive brain neurodegeneration. Mutations in ceroid lipofuscinosis neuronal protein 5 (CLN5) cause CLN5 disease, a severe condition characterized by seizures, visual failure, motor decline, and progressive cognitive deterioration. This study aimed to identify causative gene variants in Pakistani consanguineous families diagnosed with NCL. Methods After a thorough clinical and neuroradiological characterization, whole exome sequencing (WES) was performed in 3 patients from 2 unrelated families. Segregation analysis was subsequently performed through Sanger sequencing Analysis WES led to the identification of the 2 novel homozygous variants c.925_926del, (p.Leu309AlafsTer4) and c.477 T > C, (p.Cys159Arg). Conclusion In this study, we report two novel CLN5 cases in the Punjab region of Pakistan. Our observations will help clinicians observe and compare common and unique clinical features of NCL patients, further improving our current understanding of NCL.

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Pathomechanisms in the neuronal ceroid lipofuscinoses

Cited by 56 publications

References 177 publications

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis

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