Neutral Ceramidase
Introduction
Section titled “Introduction”Neutral ceramidase is an enzyme that plays a crucial role in cellular lipid metabolism, specifically within the sphingolipid pathway. Ceramides are a class of bioactive lipids involved in numerous cellular processes, including cell growth, differentiation, programmed cell death (apoptosis), and responses to stress. Neutral ceramidase (N-CDase) functions by hydrolyzing ceramides into sphingosine and a free fatty acid. This enzymatic action is vital for regulating the balance between ceramide and sphingosine-1-phosphate (S1P), two lipids with opposing effects on cell fate, thereby influencing cellular signaling pathways related to inflammation, proliferation, and survival.
Biological Basis
Section titled “Biological Basis”The activity of neutral ceramidase is primarily located in the endoplasmic reticulum and Golgi apparatus, acting at a neutral pH optimum. By converting ceramide to sphingosine,N-CDasehelps to reduce intracellular ceramide levels. Sphingosine can then be phosphorylated by sphingosine kinases to form S1P. The precise regulation of ceramide and S1P levels, mediated in part by neutral ceramidase, is fundamental for maintaining cellular homeostasis. Disruptions in this balance can lead to a variety of pathological conditions.
Clinical Relevance
Section titled “Clinical Relevance”Dysregulation of ceramide metabolism, including altered neutral ceramidase activity or levels, has been implicated in a wide range of human diseases. Elevated ceramide levels are often associated with conditions such as insulin resistance, obesity, cardiovascular diseases, and various cancers. In neurological contexts, the accumulation of ceramides has been shown to mediate oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis (ALS).[1]Therefore, measuring neutral ceramidase levels or activity can serve as a potential biomarker for these conditions, aiding in diagnosis, prognosis, and monitoring therapeutic interventions. Understanding the genetic factors influencing neutral ceramidase levels can also provide insights into individual disease susceptibility and progression. Research efforts, including large-scale proteomic studies, analyze the human blood plasma proteome to connect genetic risk to disease endpoints.[2] and to map the serum proteome to neurological diseases using whole genome sequencing.[1]These studies utilize advanced genetic and proteomic techniques to identify genetic variants that impact protein levels, offering a comprehensive view of how genes influence circulating proteins like neutral ceramidase.
Social Importance
Section titled “Social Importance”The study and of neutral ceramidase hold significant social importance due to its broad implications for human health. A deeper understanding of its biological role and clinical relevance can lead to the development of novel diagnostic tools and more effective therapeutic strategies for complex diseases. For instance, identifying individuals at risk for conditions linked to ceramide dysregulation, such as neurodegenerative diseases or metabolic disorders, could facilitate earlier interventions. Furthermore, therapies aimed at modulating neutral ceramidase activity could offer targeted approaches for disease management, ultimately improving public health outcomes and advancing personalized medicine.
Statistical and Methodological Considerations
Section titled “Statistical and Methodological Considerations”Research into neutral ceramidase levels faces several statistical and methodological challenges that can influence the robustness and interpretation of findings. For instance, the failure of certain statistical analyses, such as REML, to converge for some proteins has been attributed to limitations in sample size, potentially reducing the overall statistical power to detect associations.[1] While some studies implement rigorous adjustments for relatedness and population structure using mixed-model methods, other approaches, like linear regression, may not be robust to these factors and can produce inflated test statistics, particularly in datasets with high levels of relatedness.[3]Furthermore, the observational nature of many studies on neutral ceramidase means that randomization and blinding are not applicable, which inherently limits the ability to establish definitive causal relationships between genetic variants and neutral ceramidase levels.[4] Methodological choices also impact the reliability and replicability of findings. Different GWAS algorithms can yield varying replication rates, and some methods have been shown to be less predictive for polygenic risk scores, underscoring the need for careful method selection and validation.[3] The necessary exclusion of variants with low minor allele counts or those that fail quality control filters, while standard practice, can inadvertently limit the discovery of rarer or population-specific genetic associations. Additionally, the complex process of standardizing and transforming proteomic measurements, including accounting for batch effects and genetic ancestry components, requires extensive statistical handling, and any residual noise or uncaptured variability could affect the accuracy of the results.[5]
Generalizability and Population Diversity
Section titled “Generalizability and Population Diversity”A significant limitation in studies of neutral ceramidase involves the generalizability of findings across diverse populations. Many genetic studies have historically focused on populations of European ancestry, leading to an underrepresentation of other ethnic groups in imputation panels and genetic databases.[6]This imbalance can introduce bias, potentially overemphasizing European-specific genetic variants and limiting the transferability of findings to more diverse populations, where the genetic architecture of neutral ceramidase may differ. Efforts to account for ancestry, such as residualizing on genetic principal components, are crucial, but some studies have also found it necessary to adjust for self-reported “race” to capture non-genetic effects not fully explained by genetic ancestry alone.[5]The reliance on common variants or those present across multiple study cohorts, while useful for consistency, can lead to the exclusion of population-specific or rarer variants that might play important roles in neutral ceramidase regulation within particular groups.[6] Moreover, even when studies include diverse cohorts, differences in how genetic relatedness and non-homogeneous ancestry are modeled can lead to increased variance in false positive rate estimates, highlighting the ongoing challenges in accurately analyzing genetically diverse populations.[3]The observed lag in GWAS research for many lesser-studied populations further underscores the urgent need for increased diversity in genetic studies to ensure that insights into neutral ceramidase biology are broadly applicable.[6]
Environmental Confounders and Phenotypic Nuances
Section titled “Environmental Confounders and Phenotypic Nuances”The intricate interplay between genetic predisposition and environmental factors poses a considerable challenge to fully understanding neutral ceramidase regulation. As observational studies, research cannot fully account for all potential environmental or lifestyle confounders that might influence neutral ceramidase levels, making it difficult to isolate purely genetic effects.[4]Factors such as diet, physical activity, socio-economic status, and exposure to various environmental stressors can interact with an individual’s genetic makeup, yet these complex gene-environment interactions are often difficult to comprehensively model and measure in large-scale studies.[3]The concept of “missing heritability” suggests that even with advanced genetic analyses, a substantial portion of the heritable variation in complex traits like neutral ceramidase levels remains unexplained by identified genetic variants. This gap may be partly attributable to unmeasured environmental factors, rare genetic variants, or complex epistatic interactions that are not easily captured by current methodologies. Furthermore, the precise and standardization of neutral ceramidase levels themselves, while rigorously performed, can be affected by technical variability, such as batch effects in proteomic assays. Although researchers implement extensive quality control measures and statistical adjustments to mitigate these issues, residual technical noise or uncaptured biological variability could still impact the accuracy and interpretation of findings.[5]
Variants
Section titled “Variants”Genetic variations play a crucial role in modulating biological pathways, including lipid metabolism, which can impact neutral ceramidase activity and related cellular functions. Variants within genes directly or indirectly involved in ceramide synthesis, breakdown, or transport can alter the delicate balance of sphingolipids, influencing cellular signaling, membrane integrity, and inflammatory responses. Large-scale genetic studies have identified numerous genetic variants that influence various molecular traits and disease endpoints in human populations.[2] The ASAH2gene encodes neutral ceramidase (nCDase), an enzyme critical for the hydrolysis of ceramide into sphingosine and fatty acid. This reaction is a key step in sphingolipid metabolism, influencing the cellular balance of pro-apoptotic ceramide and pro-survival sphingosine-1-phosphate. Variants such asrs116049719 , rs10740617 , and rs10825492 within or near ASAH2may alter the expression or activity of neutral ceramidase, thereby affecting ceramide levels and downstream signaling pathways. Dysregulation of ceramide metabolism, influenced by such genetic variations, is implicated in various conditions including metabolic disorders, cardiovascular disease, and inflammation.[5] The SGMS1gene, encoding sphingomyelin synthase 1, is instrumental in converting ceramide into sphingomyelin, a major component of cell membranes. This process directly impacts the cellular ceramide pool, effectively reducing ceramide availability. Variants likers17721080 , rs146075547 , rs10763366 , rs34808309 , and rs189542721 within SGMS1could influence the efficiency of sphingomyelin synthesis, thereby indirectly affecting ceramide levels and the substrate available for neutral ceramidase. Such alterations in sphingolipid synthesis are known to impact cell membrane fluidity, receptor function, and overall cellular homeostasis.[1] Other genes contribute to the broader cellular environment that impacts ceramide metabolism. MAPK6P6 and NUTM2HP are pseudogenes, which can sometimes influence the expression of their functional counterparts or other genes through regulatory mechanisms. For instance, rs7072121 in MAPK6P6 and rs3001870 in NUTM2HP might subtly modulate gene expression profiles, indirectly affecting pathways related to lipid handling or stress responses. The ABCA6gene belongs to the ATP-binding cassette transporter family, known for transporting various molecules, including lipids, across cell membranes. The variantrs77542162 in ABCA6 could potentially alter lipid transport efficiency, influencing the availability of lipids for ceramide synthesis or clearance. Similarly, SPPL2Aencodes a signal peptide peptidase-like protease involved in intramembrane proteolysis, which can affect the processing of membrane proteins and indirectly impact membrane lipid composition or signaling, withrs8030153 potentially altering this function. These diverse genetic influences highlight the complex interplay of pathways that ultimately shape the cellular lipid landscape.[7] Further contributing to the intricate regulation of cellular metabolism are genes such as FAM21EP, OGDHL, and the LINC01252 - ETV6 locus. FAM21EP is another pseudogene, and its variants like rs114001906 , rs181888742 , and rs2338049 may exert regulatory effects on gene expression, influencing cellular processes that indirectly affect ceramide metabolism. OGDHL encodes a protein with similarity to oxoglutarate dehydrogenase, suggesting a role in mitochondrial metabolism and energy production. Variants such as rs145063180 and rs72795765 in OGDHL could impact metabolic flux, indirectly affecting the precursors or energy required for lipid synthesis and breakdown, including ceramide. The LINC01252 - ETV6 locus involves a long intergenic non-coding RNA and a transcription factor. The variant rs35764600 may influence the expression of ETV6or other nearby genes, which can have broad effects on cell development, differentiation, and metabolic regulation. Collectively, these genetic variations underscore the multifaceted genetic architecture underlying lipid homeostasis and its implications for conditions where neutral ceramidase activity is a critical determinant.[3]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs116049719 rs10740617 rs10825492 | ASAH2 | neutral ceramidase |
| rs17721080 rs146075547 rs10763366 | SGMS1 | neutral ceramidase |
| rs7072121 | MAPK6P6 | neutral ceramidase |
| rs3001870 | NUTM2HP | neutral ceramidase |
| rs77542162 | ABCA6 | low density lipoprotein cholesterol total cholesterol erythrocyte volume hematocrit hemoglobin |
| rs8030153 | SPPL2A | neutral ceramidase |
| rs114001906 rs181888742 rs2338049 | FAM21EP | neutral ceramidase |
| rs145063180 rs72795765 | OGDHL | neutral ceramidase |
| rs34808309 rs189542721 | SGMS1 | neutral ceramidase |
| rs35764600 | LINC01252 - ETV6 | neutral ceramidase triglyceride C-reactive protein saturated fatty acids to total fatty acids percentage |
Sphingolipid Metabolism and Ceramide’s Central Role
Section titled “Sphingolipid Metabolism and Ceramide’s Central Role”Sphingolipids are a diverse class of lipids crucial for cellular structure and signaling, with ceramide sitting at a central node in their metabolic pathways. Ceramide, composed of a sphingoid base and a fatty acid, is a key biomolecule that can act as a signaling molecule or be further metabolized to other sphingolipids, such as sphingomyelin or sphingosine-1-phosphate.[8]The balance between ceramide synthesis and breakdown is tightly regulated, influencing various cellular processes. Enzymes like neutral ceramidase play a critical role in hydrolyzing ceramide into sphingosine and a free fatty acid, thus modulating intracellular ceramide levels and downstream signaling.
Another important enzyme in sphingolipid metabolism is acid sphingomyelinase, which hydrolyzes sphingomyelin to ceramide.[8]This enzyme is distinct from ceramidases but highlights the dynamic interconversion of sphingolipids and the central role of ceramide. Dysregulation of these metabolic enzymes can lead to altered ceramide concentrations, impacting cellular homeostasis. Measuring neutral ceramidase levels or activity provides insight into the regulation of this crucial lipid signaling hub.
Cellular Functions and Regulatory Networks
Section titled “Cellular Functions and Regulatory Networks”Ceramide acts as a potent lipid second messenger involved in a variety of cellular functions, including cell growth arrest, differentiation, and programmed cell death (apoptosis).[9]By breaking down ceramide, neutral ceramidase can directly influence these fundamental biological processes. For instance, an accumulation of ceramides can mediate oxidative stress-induced death of motor neurons, indicating ceramide’s role in cellular demise.[9] Beyond apoptosis, ceramide and other sphingolipids are implicated in broader cellular signaling pathways and regulatory networks, including inflammation and autophagy.[10] Acid sphingomyelinase, for example, modulates the autophagic process by controlling lysosomal biogenesis.[10]Neutral ceramidase, by controlling ceramide availability, therefore indirectly affects these complex cellular responses, contributing to the overall cellular environment and its response to stress or developmental cues. The precise regulation of neutral ceramidase activity is essential for maintaining cellular balance.
Genetic Mechanisms and Expression Patterns
Section titled “Genetic Mechanisms and Expression Patterns”The activity and expression of enzymes like neutral ceramidase are subject to genetic control, influencing its overall contribution to sphingolipid metabolism. Genetic variations, such as single nucleotide polymorphisms (SNPs), can impact gene function, regulatory elements, and ultimately the expression patterns of proteins.[11]Plasma protein levels, including those of neutral ceramidase, are quantitative traits that can be linked to genetic variants through methods like genome-wide association studies (GWAS).[2] These studies aim to identify specific genetic loci associated with protein abundance, providing insights into the genetic architecture underlying enzyme levels.
Furthermore, the expression of genes encoding key biomolecules is influenced by various regulatory networks and epigenetic modifications.[2]Changes in these regulatory mechanisms can lead to altered protein levels, impacting metabolic processes and cellular functions. Understanding the genetic determinants of neutral ceramidase levels can help explain individual variability in ceramide metabolism and its susceptibility to disease. Mendelian randomization, which uses genetic variations of known function, can further examine the causal effects of modifiable exposures, such as protein levels, on disease outcomes.[7]
Pathophysiological Implications and Systemic Consequences
Section titled “Pathophysiological Implications and Systemic Consequences”Dysregulation of ceramide metabolism, particularly an imbalance in the activity of enzymes like neutral ceramidase, has significant pathophysiological consequences across various tissues and organs. An accumulation of ceramides has been linked to oxidative stress-induced cell death in neurodegenerative conditions such as amyotrophic lateral sclerosis.[9]Similarly, acid sphingomyelinase, which produces ceramide, is considered a potential therapeutic target for aging and age-related neurodegenerative diseases like Alzheimer’s disease, where it modulates autophagy and lysosomal biogenesis.[12]These findings suggest that neutral ceramidase, by counteracting ceramide accumulation, could play a protective role in such disorders. Imbalances in ceramide levels can disrupt homeostatic processes, contributing to disease mechanisms and systemic consequences beyond specific cell types. The of neutral ceramidase therefore offers a window into these intricate disease pathways and may serve as a biomarker or therapeutic target for conditions where sphingolipid metabolism is compromised.
Sphingolipid Metabolism and Ceramide Homeostasis
Section titled “Sphingolipid Metabolism and Ceramide Homeostasis”Ceramide, a central lipid second messenger, is intricately regulated within sphingolipid metabolic pathways, where its precise levels are crucial for cellular function. A key enzyme influencing ceramide levels is acid sphingomyelinase (ASM), which catalyzes the hydrolysis of sphingomyelin into ceramide and phosphocholine, primarily within lysosomes.[8]The activity of neutral ceramidase, while not explicitly detailed in its direct role, is crucial for maintaining cellular ceramide homeostasis by catabolizing ceramide into sphingosine, thus counteracting ceramide-generating pathways. This dynamic interplay ensures precise control over ceramide concentrations, which are vital for various cellular processes and can become pathogenic if dysregulated, directly impacting the flux of sphingolipid intermediates and influencing downstream signaling events.[8]
Ceramide-Mediated Cellular Signaling and Stress Responses
Section titled “Ceramide-Mediated Cellular Signaling and Stress Responses”Ceramides function as potent bioactive lipid messengers, initiating diverse intracellular signaling cascades that influence cell fate decisions. Accumulation of ceramides, often resulting from altered metabolic flux, has been directly linked to cellular stress responses, notably oxidative stress-induced death in motor neurons, as observed in amyotrophic lateral sclerosis.[9]This suggests that ceramide acts as a critical mediator in pathways leading to cellular damage and neurodegeneration. Neutral ceramidase, by modulating ceramide levels through its catabolic activity, would therefore indirectly regulate these stress-responsive pathways, impacting cellular vulnerability to oxidative insults and maintaining cellular integrity. The precise balance of ceramide generation and degradation is paramount for preventing aberrant signaling that can drive pathological processes.
Regulatory Mechanisms in Lysosomal and Autophagic Processes
Section titled “Regulatory Mechanisms in Lysosomal and Autophagic Processes”Beyond its direct metabolic role, acid sphingomyelinase (ASM) is a critical regulator of lysosomal function and the autophagic process, particularly implicated in neurodegenerative conditions like Alzheimer’s disease.[10] ASM modulates lysosomal biogenesis, influencing the cell’s ability to clear aggregated proteins and damaged organelles, a fundamental aspect of cellular quality control.[10]The levels of ceramide, subsequently acted upon by neutral ceramidase, can thus indirectly impact these vital cellular regulatory mechanisms, influencing lysosomal health and autophagic flux. Dysregulation in this integrated network, where ceramide metabolism intersects with lysosomal and autophagic pathways, represents a significant contributing factor to disease pathogenesis.
Systems-Level Dysregulation and Disease Pathogenesis
Section titled “Systems-Level Dysregulation and Disease Pathogenesis”The intricate balance of ceramide metabolism, influenced by enzymes like neutral ceramidase and acid sphingomyelinase, is subject to complex systems-level integration and can lead to significant pathway dysregulation in disease states. Alterations in ceramide levels have been identified as potential therapeutic targets for aging and age-related neurodegenerative diseases.[12] For instance, the accumulation of ceramides observed in conditions like amyotrophic lateral sclerosis underscores a failure in metabolic regulation, potentially involving insufficient ceramide catabolism or excessive production.[9]Understanding the holistic network interactions involving ceramide synthesis, degradation, and downstream signaling is crucial for identifying compensatory mechanisms and developing targeted therapeutic strategies to restore sphingolipid homeostasis and mitigate disease progression.
Clinical Relevance
Section titled “Clinical Relevance”The researchs does not contain specific information regarding the clinical relevance, prognostic value, diagnostic utility, risk assessment, or treatment monitoring strategies for neutral ceramidase. Therefore, a detailed section on its clinical applications cannot be created based on the given context.
Frequently Asked Questions About Neutral Ceramidase
Section titled “Frequently Asked Questions About Neutral Ceramidase”These questions address the most important and specific aspects of neutral ceramidase based on current genetic research.
1. Why do I gain weight easily, even when I try to be careful?
Section titled “1. Why do I gain weight easily, even when I try to be careful?”Your body’s metabolism, including how it handles fats like ceramides, is partly influenced by your genes. If your neutral ceramidase enzyme isn’t working optimally, it can lead to higher ceramide levels, which are linked to conditions like insulin resistance and obesity, making weight management tougher for you.
2. My family has a history of heart disease; am I automatically at risk?
Section titled “2. My family has a history of heart disease; am I automatically at risk?”Not automatically, but your genetic background plays a role. Variations in genes affecting neutral ceramidase activity can influence your risk for cardiovascular diseases by impacting ceramide levels. Understanding these genetic factors can offer insights into your personal susceptibility and help you take preventative steps.
3. Does stress really affect my body’s metabolism and health?
Section titled “3. Does stress really affect my body’s metabolism and health?”Yes, stress can significantly impact your metabolism. High stress levels can influence your body’s ceramide balance, and altered ceramide metabolism is linked to various health issues. While your genetics set a baseline, environmental factors like stress significantly interact with how enzymes like neutral ceramidase function.
4. Can changing my diet actually lower my risk for serious diseases?
Section titled “4. Can changing my diet actually lower my risk for serious diseases?”Absolutely. While your genes influence your baseline ceramide levels and neutral ceramidase activity, lifestyle factors like diet and exercise can significantly modulate them. Eating healthily can help maintain a healthy ceramide balance, potentially reducing your risk for conditions like metabolic disorders and certain cancers.
5. Does my ethnic background change my health risks?
Section titled “5. Does my ethnic background change my health risks?”Yes, it can. Genetic studies have often focused on specific populations, and the genetic factors influencing enzymes like neutral ceramidase can differ across ethnic groups. Your ancestry might mean you have unique genetic predispositions that affect your ceramide metabolism and overall health risks.
6. Could a blood test tell me if I’m at risk for future health problems?
Section titled “6. Could a blood test tell me if I’m at risk for future health problems?”Potentially, yes. Measuring levels or activity of enzymes like neutral ceramidase in your blood is being explored as a potential biomarker. This could help identify individuals at higher risk for conditions like metabolic or neurological diseases, allowing for earlier interventions and personalized health strategies.
7. Why do some treatments work for my friends but not for me?
Section titled “7. Why do some treatments work for my friends but not for me?”Your unique genetic makeup, including variations in enzymes like neutral ceramidase, can influence how your body responds to therapies. What works for one person might not be as effective for another due to these underlying genetic differences impacting ceramide metabolism. This highlights the importance of personalized medicine.
8. If I exercise consistently, can I overcome my ‘bad’ genes?
Section titled “8. If I exercise consistently, can I overcome my ‘bad’ genes?”Exercise is incredibly beneficial and can significantly influence your health, even with genetic predispositions. While your genetics set a certain baseline for ceramide metabolism, a healthy lifestyle, including regular physical activity, can help regulate these pathways and reduce disease risk. It’s a powerful tool for managing your genetic hand.
9. Is there a connection between my brain health and my body’s metabolism?
Section titled “9. Is there a connection between my brain health and my body’s metabolism?”Yes, there’s a growing understanding of this link. For example, ceramide accumulation, influenced by enzymes like neutral ceramidase, has been implicated in neurological conditions such as ALS, where it can lead to nerve cell death. Maintaining a healthy metabolic balance is crucial for optimal brain function.
10. If I have certain health risks, will my kids definitely get them too?
Section titled “10. If I have certain health risks, will my kids definitely get them too?”Not necessarily “definitely,” but your children can inherit genetic predispositions that influence their risk for similar conditions. Genes affecting enzymes like neutral ceramidase are passed down, impacting how their bodies manage ceramides, which in turn affects their susceptibility to certain diseases. Lifestyle choices will also play a crucial role in their health outcomes.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Png, G. et al. “Mapping the serum proteome to neurological diseases using whole genome sequencing.” Nat Commun, vol. 12, no. 1, 2021, p. 7000.
[2] Suhre, K. et al. “Connecting genetic risk to disease end points through the human blood plasma proteome.”Nat Commun, vol. 8, 2017, p. 14357.
[3] Loya, Hélène, et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics, vol. 57, no. 2, 2025, pp. 461-468.
[4] Dhindsa, R. S., et al. “Rare variant associations with plasma protein levels in the UK Biobank.” Nature, 2023.
[5] Katz, D. H., et al. “Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease.” Circulation, vol. 144, no. 22, 2021, pp. 1779-1793.
[6] Thareja, Gaurav, et al. “Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations.” Human Molecular Genetics, vol. 32, no. 6, 2023, pp. 993-1006.
[7] Yang, C., et al. “Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders.” Nat. Neurosci., vol. 24, no. 8, 2021, pp. 1192-1205.
[8] Jenkins, R. W., Canals, D. & Hannun, Y. A. Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell. Signal. 21, 836–846 (2009).
[9] Cutler, R. G., et al. “Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis.” Ann. Neurol., vol. 52, no. 4, 2002, pp. 448–457.
[10] Lee, J. K. et al. Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer’s disease. J. Exp. Med. 211, 1551–1570 (2014).
[11] Yang, J., et al. “Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index.” Nat. Genet., vol. 47, no. 10, 2015, pp. 1114–1120.
[12] Park, M. H., et al. “Potential therapeutic target for aging and age-related neurodegenerative diseases: the role of acid sphingomyelinase.” Exp. Mol. Med., vol. 52, no. 3, 2020, pp. 380–389.