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Published on: March 11, 2020
Diminished hippocalcin expression in Huntington's disease brain does not account for increased striatal neuron
Nikita Rudinskiy1, Yoshio A Kaneko, Ayshe Ana Beesen
1Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Insights
Reduced hippocalcin levels do not cause neurodegeneration in Huntington's disease (HD). Restoring hippocalcin expression did not protect striatal neurons in HD cellular models, indicating it is not a key factor in HD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Hippocalcin is a neuronal calcium sensor protein.
- It is highly expressed in medium spiny striatal output neurons, which are affected in Huntington's disease (HD).
- Previous studies showed decreased hippocalcin expression in HD mouse models.
Purpose of the Study:
- To investigate the role of hippocalcin in Huntington's disease (HD) pathogenesis.
- To determine if diminished hippocalcin expression contributes to striatal neurodegeneration in HD.
- To test if restoring hippocalcin levels can protect against HD-related neurodegeneration.
Main Methods:
- In situ hybridization histochemistry to quantify hippocalcin RNA in human HD brain samples.
- Cellular models of HD using primary striatal neurons exposed to mutant huntingtin, 3-nitropropionic acid, or glutamate.
- Assessing neuroprotection by restoring hippocalcin expression, alone or with interactors like neuronal apoptosis inhibitory protein.
Main Results:
- Hippocalcin RNA was diminished by 63% in human HD brain.
- Restoration of hippocalcin expression did not improve striatal neuron survival under HD-related stress conditions.
- Co-expression of hippocalcin with interactors did not enhance neuronal survival in HD cellular models.
Conclusions:
- Diminished hippocalcin expression does not contribute to striatal neurodegeneration in Huntington's disease (HD).
- Hippocalcin is unlikely to be a therapeutic target for HD based on these findings.
Abstract:
Hippocalcin is a neuronal calcium sensor protein previously implicated in regulating neuronal viability and plasticity. Hippocalcin is the most highly expressed neuronal calcium sensor in the medium spiny striatal output neurons that degenerate selectively in Huntington's disease (HD). We have previously shown that decreased hippocalcin expression occurs in parallel with the onset of disease phenotype in mouse models of HD. Here we show by in situ hybridization histochemistry that hippocalcin RNA is also diminished by 63% in human HD brain. These findings lead us to hypothesize that diminished hippocalcin expression might contribute to striatal neurodegeneration in HD. We tested this hypothesis by assessing whether restoration of hippocalcin expression would decrease striatal neurodegeneration in cellular models of HD comprising primary striatal neurons exposed to mutant huntingtin, the mitochondrial toxin 3-nitropropionic acid or an excitotoxic concentration of glutamate. Counter to our hypothesis, hippocalcin expression did not improve the survival of striatal neurons under these conditions. Likewise, expression of hippocalcin together with interactor proteins including the neuronal apoptosis inhibitory protein did not increase the survival of striatal cells in cellular models of HD. These results indicate that diminished hippocalcin expression does not contribute to HD-related neurodegeneration.
