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Proposed model linking calmodulin to neuronal ceroid lipofuscinosis. Altered levels of intracellular calcium underlie neuronal ceroid lipofuscinosis (NCL). Since calmodulin (CaM) is the primary downstream target of calcium, in turn, its binding proteins (i.e., CaMBPs) will be involved in facets of the disease. Eleven proteins linked to NCL contain putative CaM-binding domains (CaMBDs) (CLN1-6, CLN8, CLN10, and CLN12-14), suggesting a direct interaction with CaM. Cathepsin L (CTSL), an enzyme that processes CLN7 and CLN11, also contains a CaMBD. Thus, CaM is capable of directly regulating the NCL proteins or indirectly regulating them through CTSL. Mutations in NCL proteins affect neuronal function and results in neurodegeneration. Arrows indicate the links between calcium, CaM, the NCL proteins, and NCL. ‡ Non-NCL protein.
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Despite the increased focus on the role of calcium in the neuronal ceroid lipofuscinoses (NCLs, also known as Batten disease), links between calcium signalling and the proteins associated with the disease remain to be identified. A central protein in calcium signalling is calmodulin (CaM), which regulates many of the same cellular processes affecte...
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... interactions with CaM are possible for 11 of the 13 NCL proteins (Figure 2), whereas it would likely occur through an indirect interaction via CTSL (Figure 2) if CaM were to regulate CLN7 and CLN11. Our findings indicate that the NCL proteins converge with CaM, which may serve to regulate their functions (Figure 2). ...
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... interactions with CaM are possible for 11 of the 13 NCL proteins (Figure 2), whereas it would likely occur through an indirect interaction via CTSL (Figure 2) if CaM were to regulate CLN7 and CLN11. Our findings indicate that the NCL proteins converge with CaM, which may serve to regulate their functions (Figure 2). ...
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... interactions with CaM are possible for 11 of the 13 NCL proteins (Figure 2), whereas it would likely occur through an indirect interaction via CTSL (Figure 2) if CaM were to regulate CLN7 and CLN11. Our findings indicate that the NCL proteins converge with CaM, which may serve to regulate their functions (Figure 2). In NCL patients, the altered levels of intracellular calcium could influence processes regulated by CaM. ...
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The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating neurological disorders that have a global distribution and affect people of all ages. Commonly known as Batten disease, this form of neurodegeneration is linked to mutations in 13 genetically distinct genes. The precise mechanisms underlying the disease are unknown, in large part...
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... Altogether, several studies on infantile and late infantile variants mentioned abnormal lipid metabolism 3 , and others noted changes in the composition of various phospholipid and ceramides classes 38,42,43 (Table 4), yet our work is the first to link the sphingolipid metabolism to CLN6. Furthermore, the role of calcium signaling has been investigated in several models showing an important role of calcium homeostasis in NCL pathology 44,45 and elevated calcium-binding protein calbindin 1 (CALB1) levels in cerebrospinal fluid from CLN2 and CLN3 disease patients 46 . Similarly, our study found that the downregulation of glucosylceramides, cyclic ADP-ribose, and vitamin K1 was associated with the inhibition of calcium signaling in CLN6 disease. ...
Neuronal ceroid lipofuscinosis 6 (CLN6) is a rare and fatal autosomal recessive disease primarily affecting the nervous system in children. It is caused by a pathogenic mutation in the CLN6 gene for which no therapy is available. Employing an untargeted metabolomics approach, we analyzed the metabolic changes in CLN6 subjects to see if this system could potentially yield biomarkers for diagnosis and monitoring disease progression. Neuronal-like cells were derived from human fibroblast lines from CLN6-affected subjects (n = 3) and controls (wild type, n = 3). These were used to assess the potential of a neuronal-like cell-based metabolomics approach to identify CLN6 distinctive and specific biomarkers. The most impacted metabolic profile is associated with sphingolipids, glycerophospholipids metabolism, and calcium signaling. Over 2700 spectral features were screened, and fifteen metabolites were identified that differed significantly between both groups, including the sphingolipids C16 GlcCer, C24 GlcCer, C24:1 GlcCer and glycerophospholipids PG 40:6 and PG 40:7. Of note, these fifteen metabolites were downregulated in the CLN6 disease group. This study is the first to analyze the metabolome of neuronal-like cells with a pathogenic mutation in the CLN6 gene and to provide insights into their metabolomic alterations. This could allow for the development of novel biomarkers for monitoring CLN6 disease.
... Its progressive nature and fatal outcome represent a heavy burden for the families of affected children and for society. CLN3 has been linked to a variety of different processes, such as regulation of lysosomal pH 32,33 , autophagy 34,35 , calcium homeostasis 36,37 , cell proliferation 38,39 and synaptic activity 12 , and it was recently shown to be essential for the clearance of glycerophosphodiesters from lysosomes 40 . More recently, attention has shifted to the ability of CLN3 to modulate endocytic pathways and membrane dynamics [41][42][43] , suggesting that this protein may exert a global role on lysosomal function. ...
Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease.
... apolipoprotein E (APOE) is a neuroinflammatory risk factor CaMBP for AD, ALS, FTD, LBD and PD but not HD or MS. APOE has also been linked to BD, a family of neurodegenerative disorders clinically known as the neuronal ceroid lipofuscinoses (NCLs), in which CaMBPs have been predicted to play a significant role [25,52]. In addition, there is strong genetic overlap of the NCLs with AD, PD, and FTD [2,11,14,16,49,62]. ...
Calcium dysregulation (“Calcium Hypothesis”) is an early and critical event in Alzheimer’s and other neurodegenerative diseases. Calcium binds to and regulates the small regulatory protein calmodulin that in turn binds to and regulates several hundred calmodulin binding proteins. Initial and continued research has shown that many calmodulin binding proteins mediate multiple events during the onset and progression of Alzheimer’s disease, thus establishing the “Calmodulin Hypothesis”. To gain insight into the general applicability of this hypothesis, the involvement of calmodulin in neuroinflammation in Alzheimer’s, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, frontotemporal dementia, and other dementias was explored. After a literature search for calmodulin binding, 11 different neuroinflammatory proteins (TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, ABCA1, CH3L1/YKL-40 and NLRP3) were scanned for calmodulin binding domains using the Calmodulin Target Database. This analysis revealed the presence of at least one binding domain within which visual scanning demonstrated the presence of valid binding motifs. Coupled with previous research that identified 13 other neuroinflammation linked proteins (BACE1, BIN1, CaMKII, PP2B, PMCA, NOS, NMDAR, AchR, Ado A2AR, Aβ, APOE, SNCA, TMEM175), this work shows that at least 24 critical proteins involved in neuroinflammation are putative or proven calmodulin binding proteins. Many of these proteins are linked to multiple neurodegenerative diseases indicating that calmodulin binding proteins lie at the heart of neuroinflammatory events associated with multiple neurodegenerative diseases. Since many calmodulin-based pharmaceuticals have been successfully used to treat Huntington’s and other neurodegenerative diseases, these findings argue for their immediate therapeutic implementation.
... 48 Indeed, in CLN3 disease, Ca ++ signaling has been reported to be defective 49 and interestingly, calmodulin which is a major facilitator of Ca ++ signaling pathway regulates some of the same cellular processes affected in the NCLs. 50 Since we found that the level of p-NFATC4 in Ppt1 À/À mouse brain was substantially higher than that in WT littermates, we determined the levels of calcineurin-and calmodulin-protein levels, respectively, in the brain of Ppt1 À/À mice. We found that the levels of both proteins were significantly lower in Ppt1 À/À mice ( Figure 4G,H). ...
Inactivating mutations in the PPT1 gene encoding palmitoyl‐protein thioesterase‐1 (PPT1) underlie the CLN1 disease, a devastating neurodegenerative lysosomal storage disorder. The mechanism of pathogenesis underlying CLN1 disease has remained elusive. PPT1 is a lysosomal enzyme, which catalyzes the removal of palmitate from S‐palmitoylated proteins (constituents of ceroid lipofuscin) facilitating their degradation and clearance by lysosomal hydrolases. Thus, it has been proposed that Ppt1‐deficiency leads to lysosomal accumulation of ceroid lipofuscin leading to CLN1 disease. While S‐palmitoylation is catalyzed by palmitoyl acyltransferases (called ZDHHCs), palmitoyl‐protein thioesterases (PPTs) depalmitoylate these proteins. We sought to determine the mechanism by which Ppt1‐deficiency may impair lysosomal degradative function leading to INCL pathogenesis. Here we report that in Ppt1−/− mice, which mimic CLN1 disease, low level of inositol 3‐phosphate receptor‐1 (IP3R1) that mediates Ca++‐transport from the ER to the lysosome dysregulated lysosomal Ca++ homeostasis. Intriguingly, the transcription factor NFATC4, which regulates IP3R1‐expression, required S‐palmitoylation for trafficking from the cytoplasm to the nucleus. We identified two palmitoyl acyltransferases, ZDHHC4 and ZDHHC8, which catalyzed S‐palmitoylation of NFATC4. Notably, in Ppt1−/− mice, reduced ZDHHC4 and ZDHHC8 levels markedly lowered S‐palmitoylated NFATC4 (active) in the nucleus, which inhibited IP3R1‐expression, thereby, dysregulating lysosomal Ca++ homeostasis. Consequently, Ca++‐dependent lysosomal enzyme activities were markedly suppressed. Impaired lysosomal degradative function impaired autophagy, which caused lysosomal storage of undigested cargo. Importantly, IP3R1‐overexpression in Ppt1−/− mouse fibroblasts ameliorated this defect. Our results reveal a previously unrecognized role of Ppt1 in regulating lysosomal Ca++‐homeostasis and suggest that this defect contributes to pathogenesis of CLN1 disease. This article is protected by copyright. All rights reserved.
... 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]. ...
... 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]. ...
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.
... 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). ...
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.
... Inside autolysosomes, the hydrolysis of the autophagic macromolecules into their building blocks by hydrolases enzymes occur to allow recycling them back to cytosol. The transition to mitochondrial permeability conversion pore to an open state leads to mitochondrial degradation by macroautophagy and thereafter necrosis and apoptosis (Didac et al., 2018;Sabateeshan et al., 2018). Then, macroautophagy protects oxidative damage cells that results from mitochondrial integrity loss without apoptosis triggering (Dawson and Cho, 2000). ...
Autophagy is a survival process in which a cell preserves its components in case of nutrient deprivation by recycling its digested contents and cannibalizing itself. It is characterized by formation of double membrane autophagosomes and it has a role in cancer treatment by many mechanisms. Interestingly, autophagy has a significant effect in the treatment of many diseases by different mechanisms. Autophagy has been included as a treatment mechanism of various diseases, such as degenerative diseases of the muscle and nervous system. Abundant autophagic vacuoles were formed inside the damaged cells in many of these degenerative disorders. Autophagy can help both living cells and cancer cells to survive so some antitumor agents targeted autophagy in cancer cells. In this review, we illustrated the definition of autophagy, autophagic pathways, therapeutic implications of autophagy in cancer, the relationship between autophagy and cell death, inflammation, and necrosis.
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.
