. Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity. Cell Rep. 2019 Apr 2;27(1):59-70.e4. PubMed.


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  1. This is an interesting paper, and I think it is well-conducted and meaningful.

    An important takeaway is that circadian regulation of cellular function is complex, and the effects of clock disruption on measures of disease may be highly context-dependent. While it may be tempting to assume that disrupting the normal timing system has all negative effects in the brain, this may not be true. Certainly we know that disrupting different clock genes can have very different effects on processes such as inflammation and carcinogenesis, as the clock has both positive and negative transcriptional regulators, and individual clock genes have unique cellular functions. I am not surprised that disrupting the clock in neurons causes a stress response (as we and others have shown that the clock regulates cellular oxidative stress), and in this case, in these cells, in this animal, induces a heat shock protein. What is surprising is that this heat shock protein, Hop, seems to exacerbate Htt toxicity. That may be something unique about Hop and the type of aggregates that it binds or promotes, but that is outside my purview. However, the idea that clock disruption could have “conflicting” effects on neurodegeneration depending on the model and cell type is something that we must investigate, and is in keeping with unpublished mouse data from my lab. Thus, I think this paper illustrates the intricacies of the circadian clock and its multitude of effects, and suggest that we need a deeper understand of how circadian system regulate different aspects of neurodegeneration.

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