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Cause or compensation?-Altered neuronal Ca2+ handling in Huntington's disease
James P Mackay1, Wissam B Nassrallah1,2, Lynn A Raymond1
1Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
Huntington's disease (HD) involves neurodegeneration, particularly in specific neurons. This study explores how altered calcium (Ca2+) handling, influenced by mutant huntingtin protein (mHTT), contributes to HD pathogenesis and potential therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder with no current disease-modifying treatments.
- Medium-sized spiny projection neurons (SPNs) in the caudate and putamen are severely affected in HD, but the reasons for this selectivity and late-onset symptoms remain unclear.
- Mutant huntingtin protein (mHTT) interacts with neuronal proteins, leading to altered cellular processes, including calcium (Ca2+) handling.
Purpose of the Study:
- To investigate the role of altered neuronal calcium (Ca2+) handling in Huntington's disease (HD) pathogenesis.
- To determine if specific Ca2+ handling alterations, involving NMDA receptors, IP3 receptors, and mitochondria, are early events in HD.
- To assess the potential of reversing these Ca2+ handling alterations as a therapeutic strategy for HD.
Main Methods:
- Focused on extrasynaptic NMDA-type glutamate receptors, endoplasmic reticulum IP3 receptors, and mitochondria.
- Examined the interaction between mutant huntingtin protein (mHTT) and Ca2+ handling pathways.
- Reviewed evidence for early disease manifestation and disease-modifying potential of interventions in animal models.
Main Results:
- Altered neuronal Ca2+ influx and intracellular Ca2+ handling are prominent features in HD models.
- Some compensatory processes, like store-operated Ca2+ channel responses, may paradoxically contribute to HD pathogenesis.
- Evidence suggests that specific Ca2+ handling alterations interact with mHTT and may be reversed in animal models to modify disease progression.
Conclusions:
- A causation-based approach is crucial for understanding the link between mHTT and neurodegeneration in HD.
- Early alterations in Ca2+ handling are implicated in HD pathogenesis and interact with mHTT.
- Targeting and reversing aberrant Ca2+ handling mechanisms show promise as a potential therapeutic strategy for Huntington's disease.
Abstract:
Huntington's disease (HD) is a hereditary neurodegenerative disorder of typically middle-aged onset for which there is no disease-modifying treatment. Caudate and putamen medium-sized spiny projection neurons (SPNs) most severely degenerate in HD. However, it is unclear why mutant huntingtin protein (mHTT) is preferentially toxic to these neurons or why symptoms manifest only relatively late in life. mHTT interacts with numerous neuronal proteins. Likewise, multiple SPN cellular processes have been described as altered in various HD models. Among these, altered neuronal Ca2+ influx and intracellular Ca2+ handling feature prominently and are addressed here. Specifically, we focus on extrasynaptic NMDA-type glutamate receptors, endoplasmic reticulum IP3 receptors, and mitochondria. As mHTT is expressed throughout development, compensatory processes will likely be mounted to mitigate any deleterious effects. Although some compensations can lessen mHTT's disruptive effects, others-such as upregulation of the ER-refilling store-operated Ca2+ channel response-contribute to pathogenesis. A causation-based approach is therefore necessary to decipher the complex sequence of events linking mHTT to neurodegeneration, and to design rational therapeutic interventions. With this in mind, we highlight evidence, or lack thereof, that the above alterations in Ca2+ handling occur early in the disease process, clearly interact with mHTT, and show disease-modifying potential when reversed in animals.