Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

Mathavarajah, Sabateeshan; O’Day, Danton H.; Huber, Robert J.

doi:10.3390/cells7110188

Cited by 11 publications

(8 citation statements)

References 47 publications

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“…The identification of NagA and CtsD in Dictyostelium CaM IP fractions suggests that CaM-mediated signalling may play an important role in the pathology underlying both diseases. Consistent with these findings, previous work identified two regions in human CTSD that contain putative CaMBDs [ 11 ]. In addition, CTSD function has been linked to calcineurin, a known CaMBP in humans [ 52 ].…”

Section: Discussionsupporting

confidence: 81%

“…As a result, CaM and CaMBPs are associated with several essential processes in eukaryotic cells such as autophagy, apoptosis, cell cycle progression, cell proliferation, cell differentiation, and cytoskeletal organization [ 8 ]. Not surprisingly, CaM and CaMBPs have been linked to several human diseases including Alzheimer’s disease, heart disease, and the neuronal ceroid lipofuscinoses (NCLs, commonly known as Batten disease) [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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A Proteomics Analysis of Calmodulin-Binding Proteins in Dictyostelium discoideum during the Transition from Unicellular Growth to Multicellular Development

Kim

Yap

Huber

2021

IJMS

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Calmodulin (CaM) is an essential calcium-binding protein within eukaryotes. CaM binds to calmodulin-binding proteins (CaMBPs) and influences a variety of cellular and developmental processes. In this study, we used immunoprecipitation coupled with mass spectrometry (LC-MS/MS) to reveal over 500 putative CaM interactors in the model organism Dictyostelium discoideum. Our analysis revealed several known CaMBPs in Dictyostelium and mammalian cells (e.g., myosin, calcineurin), as well as many novel interactors (e.g., cathepsin D). Gene ontology (GO) term enrichment and Search Tool for the Retrieval of Interacting proteins (STRING) analyses linked the CaM interactors to several cellular and developmental processes in Dictyostelium including cytokinesis, gene expression, endocytosis, and metabolism. The primary localizations of the CaM interactors include the nucleus, ribosomes, vesicles, mitochondria, cytoskeleton, and extracellular space. These findings are not only consistent with previous work on CaM and CaMBPs in Dictyostelium, but they also provide new insight on their diverse cellular and developmental roles in this model organism. In total, this study provides the first in vivo catalogue of putative CaM interactors in Dictyostelium and sheds additional light on the essential roles of CaM and CaMBPs in eukaryotes.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

A Proteomics Analysis of Calmodulin-Binding Proteins in Dictyostelium discoideum during the Transition from Unicellular Growth to Multicellular Development

Kim

Yap

Huber

2021

IJMS

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“…However, other affected proteins appeared to be specific for certain subtypes of NCL. Calcium signaling is thought to play an important role in NCL pathology ( Mathavarajah et al, 2018b ) and the calcium-binding protein calbindin 1 (CALB1) was significantly elevated in CSF from CLN2 and CLN3 disease patients ( Sleat et al, 2017 ). Increased amounts of CALB1 have also been reported in CSF obtained from patients with Niemann–Pick type C1 disease, another lysosomal storage disease ( Bradbury et al, 2016 ).…”

Section: Potential Biomarkers Identified In Animal Models and Humansmentioning

confidence: 99%

Altered protein secretion in Batten disease

Huber

2021

Disease Models &Amp; Mechanisms

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The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

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“…Initially recognized for studies on fundamental biological processes, more recently it has been used a biomedical model for research into autophagy, cell stress, extracellular vesicles, osmoregulation, wound healing, neurodegenerative diseases, and mitochondrial diseases, among others (e.g. Annesley & Fisher, Annesley & Fisher, 2001;Huber, 2016;Mathavarajah, O'Day, & Huber, 2018b;Dunn et al, 2018;Myre, Huber, & O'Day, 2018;Tatischeff, 2019).…”

Section: Introductionmentioning

confidence: 99%

Calmodulin‐mediated events during the life cycle of the amoebozoan Dictyostelium discoideum

et al. 2019

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This review focusses on the functions of intracellular and extracellular calmodulin, its target proteins and their binding proteins during the asexual life cycle of Dictyostelium discoideum. Calmodulin is a primary regulatory protein of calcium signal transduction that functions throughout all stages. During growth, it mediates autophagy, the cell cycle, folic acid chemotaxis, phagocytosis, and other functions. During mitosis, specific calmodulin‐binding proteins translocate to alternative locations. Translocation of at least one cell adhesion protein is calmodulin dependent. When starved, cells undergo calmodulin‐dependent chemotaxis to cyclic AMP generating a multicellular pseudoplasmodium. Calmodulin‐dependent signalling within the slug sets up a defined pattern and polarity that sets the stage for the final events of morphogenesis and cell differentiation. Transected slugs undergo calmodulin‐dependent transdifferentiation to re‐establish the disrupted pattern and polarity. Calmodulin function is critical for stalk cell differentiation but also functions in spore formation, events that begin in the pseudoplasmodium. The asexual life cycle restarts with the calmodulin‐dependent germination of spores. Specific calmodulin‐binding proteins as well as some of their binding partners have been linked to each of these events. The functions of extracellular calmodulin during growth and development are also discussed. This overview brings to the forefront the central role of calmodulin, working through its numerous binding proteins, as a primary downstream regulator of the critical calcium signalling pathways that have been well established in this model eukaryote. This is the first time the function of calmodulin and its target proteins have been documented through the complete life cycle of any eukaryote.

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Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

Cited by 11 publications

References 47 publications

A Proteomics Analysis of Calmodulin-Binding Proteins in Dictyostelium discoideum during the Transition from Unicellular Growth to Multicellular Development

A Proteomics Analysis of Calmodulin-Binding Proteins in Dictyostelium discoideum during the Transition from Unicellular Growth to Multicellular Development

Altered protein secretion in Batten disease

Calmodulin‐mediated events during the life cycle of the amoebozoan Dictyostelium discoideum

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