Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases
Abstract
:1. Introduction
2. The Role of Lysosomes in Protein Homeostasis
3. The Role of the Lysosomal Degradation System in Neurodegenerative Diseases
4. The Role of Lysosomes in Lipid Homeostasis
5. Failure of Lipid Degradation Leads to Lipidosis
6. Commonalities Between Sphingolipidosis and Neurodegenerative Diseases
6.1. GBA1
6.2. NPC1
6.3. SMPD1
6.4. GALC
6.5. GRN
7. Genetic Screens Reveal Regulators of Lipid and Protein Homeostasis
8. Dose-Dependent Effects and the Aging Brain
9. Conclusions
10. Outlook
- Leverage lipidomics for biomarker discovery: High-resolution lipid profiling holds promise for identifying early diagnostic and prognostic markers of neurodegenerative diseases. Achieving this goal will require the standardization of lipidomics methodologies across laboratories and platforms.
- Investigate the role of lipid droplets in neural cells: Accumulation of lipid droplets in neurons and glia has been linked to neurodegeneration [109]. Understanding the dynamics and function of lipid droplets could uncover new therapeutic targets.
- Evaluate the therapeutic potential of fatty acid substitution, including polyunsaturated fatty acids: Dietary supplementation with, e.g., polyunsaturated fatty acids may help rebalance lipid metabolism and reduce neuroinflammation, particularly in aging and early disease stages.
- Understanding disease specificity: Several lysosomal genes have been linked to distinct neurodegenerative diseases (e.g., GBA1 to PD, GRN to FTD), but the basis for this specificity remains unclear. Future work should explore how factors such as particular lipid metabolites, cell type, or potential regional differences in brain lipid composition might influence which disease phenotype emerges in response to a given lysosomal defect.
- Clarify the interplay between genetic and environmental factors in lipid–protein homeostasis: Determining how risk genes and environmental stressors influence lipostasis and proteostasis in neurons will be essential for identifying susceptible populations and designing preventive interventions.
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Gene | Lipid Storage Disorder | Lipid Accumulation or Imbalance | Neurodegeneration-Linked Pathology | Shared Mechanisms |
---|---|---|---|---|
GBA1 | Gaucher disease | glucosylceramide, glucosylsphingosine | ↑ PD risk; α-synuclein aggregation and transmission | autophagy impairment, lysosomal rupture, proteostasis failure |
NPC1 | Niemann–Pick type C | unesterified cholesterol, glycosphingolipids | lysosomal rupture; debated PD association | autophagy impairment, lysosomal enzyme mistrafficking, membrane rupture |
SMPD1 | Niemann–Pick type A/B | sphingomyelin | ↑ PD risk (variants) | autophagy impairment, lysosomal stress |
GALC | Krabbe disease | psychosine (galactosyl-sphingosine) | ↑ PD risk; aggregation and prion-like propagation of α-synuclein | lysosomal stress and membrane destabilization |
GRN | NCL and GRN-FTD | glucosylceramide; loss of myelin lipids (e.g., sulfatide) | TDP-43 aggregation, cortical neuronal loss; ↑ AD and PD risk | disrupted GCase activity (see GBA1), myelin loss |
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Tittelmeier, J.; Nussbaum-Krammer, C. Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases. Cells 2025, 14, 845. https://doi.org/10.3390/cells14110845
Tittelmeier J, Nussbaum-Krammer C. Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases. Cells. 2025; 14(11):845. https://doi.org/10.3390/cells14110845
Chicago/Turabian StyleTittelmeier, Jessica, and Carmen Nussbaum-Krammer. 2025. "Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases" Cells 14, no. 11: 845. https://doi.org/10.3390/cells14110845
APA StyleTittelmeier, J., & Nussbaum-Krammer, C. (2025). Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases. Cells, 14(11), 845. https://doi.org/10.3390/cells14110845