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Published on: February 27, 2018
Sphingolipids and impaired hypoxic stress responses in Huntington disease
Johannes Burtscher1, Giuseppe Pepe2, Niran Maharjan3
1Institute of Sport Sciences, University of Lausanne, 1015 Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, 1005 Lausanne, Switzerland.
Insights
Huntington disease (HD) involves sphingolipid alterations and impaired cellular stress responses, particularly hypoxia. Targeting these pathways offers novel therapeutic strategies for this incurable neurodegenerative disorder.
Area of Science:
- Neurodegenerative Diseases
- Cellular Metabolism
- Molecular Biology
Background:
- Huntington disease (HD) is a fatal, incurable neurodegenerative disorder.
- Protein aggregation and metabolic deficits are key pathological features, but their link to neurodegeneration is debated.
- Sphingolipids play critical roles in cellular homeostasis and stress responses.
Purpose of the Study:
- To characterize sphingolipid patterns specific to Huntington disease.
- To investigate the role of sphingolipids in cellular homeostasis and stress responses in HD.
- To explore sphingolipids as potential therapeutic targets for HD.
Main Methods:
- Review of existing literature on sphingolipid metabolism in HD.
- Analysis of sphingolipid alterations in the context of cellular stress, including hypoxia.
- Evaluation of conditioning approaches and sphingolipid modulation for improving cellular resilience.
Main Results:
- Sphingolipid alterations are identified as a potential molecular hallmark of Huntington disease.
- Hypothesized link between maladaptive sphingolipid regulation during cellular stress (hypoxia) and HD pathology.
- Sphingolipids influence cellular energy metabolism and proteostasis, functions potentially impaired in HD.
Conclusions:
- Sphingolipid metabolism is vital for cellular adaptation to stress, including hypoxia.
- Inadequate cellular response to hypoxic stress, mediated by sphingolipids, likely contributes to HD progression.
- Targeting sphingolipids and hypoxic stress responses presents novel therapeutic avenues for Huntington disease.
Abstract:
Huntington disease (HD) is a debilitating, currently incurable disease. Protein aggregation and metabolic deficits are pathological hallmarks but their link to neurodegeneration and symptoms remains debated. Here, we summarize alterations in the levels of different sphingolipids in an attempt to characterize sphingolipid patterns specific to HD, an additional molecular hallmark of the disease. Based on the crucial role of sphingolipids in maintaining cellular homeostasis, the dynamic regulation of sphingolipids upon insults and their involvement in cellular stress responses, we hypothesize that maladaptations or blunted adaptations, especially following cellular stress due to reduced oxygen supply (hypoxia) contribute to the development of pathology in HD. We review how sphingolipids shape cellular energy metabolism and control proteostasis and suggest how these functions may fail in HD and in combination with additional insults. Finally, we evaluate the potential of improving cellular resilience in HD by conditioning approaches (improving the efficiency of cellular stress responses) and the role of sphingolipids therein. Sphingolipid metabolism is crucial for cellular homeostasis and for adaptations following cellular stress, including hypoxia. Inadequate cellular management of hypoxic stress likely contributes to HD progression, and sphingolipids are potential mediators. Targeting sphingolipids and the hypoxic stress response are novel treatment strategies for HD.
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