Enhancing the brain’s clean up crews

Enhancing the brain’s own clean-up crews could be a strategy for handling the toxic proteins driving several neurodegenerative diseases, new research suggests.

Astrocytes, an abundant supportive cell type in the brain, are better than neurons at disposing of mutant huntingtin, the toxic protein that drives Huntington’s disease pathology, Xiao-Jiang Li and colleagues report in this week’s PNAS.

One reason why astrocytes are better at toxic protein defense than neurons is: they have less of an inhibitory protein called HspBP1. The scientists show that using CRISPR/Cas9 to “knock down” HspBP1 can help neurons get rid of mutant huntingtin and reduce early pathological signs.

The knock down experiments were done in a mouse model of Huntington’s disease. However, in this paper, Li and his team did not show effects on mouse motor abilities, like they did in their June 2017 Journal of Clinical Investigation paper, which was featured on NBC Nightly News. The JCI paper describes how CRISPR/Cas9 gene editing enzymes, delivered by viral vector, can snip out part of the gene encoding mutant huntingtin, also in a mouse model. (This 2016 PLOS Genetics paper delves into what part should get cut out.)

In astrocytes, CHIP (red) colocalizes with mutant huntingtin (green). Cell nuclei are blue.

The newer findings sketch out an intervention – targeting HspBP1 — that could be relevant for other neurodegenerative diseases as well.

What HspBP1 inhibits is another protein called CHIP, a key part of the cell’s cleanup crew. CHIP finds misfolded proteins and decorates them with a tag called ubiquitin, which is a garbage disposal signal. CHIP also boosts levels of Hsp70, a “chaperone” that keeps misfolded proteins from aggregating. The Li lab showed that CHIP is important for astrocytes’ superior response to elevated temperatures, and is involved in degrading several proteins connected with neurodegenerative diseases.

Examples include: TDP-43 (frontotemporal dementia and ALS), TBP (mutated in a form of spinocerebellar ataxia), and alpha-synuclein (Parkinson’s disease)

Xiao-Jiang Li comments:

“Our work used cell cultures and suggested that CHIP ubiquitin ligase is involved in promoting the degradation of various disease proteins. Other published studies have found that it also can detoxify aggregated huntingtin protein.  Whether it has similar effects on the toxicity of other disease proteins remains to be investigated.”

What this paper does not address is whether HspBP1 has some positive function in neurons, and thus whether targeting it would have harmful side effects. Li notes that HspBP1 knockout mice, established by another lab, are viable and do not show neuronal damage, although the males do have fertility problems.

Li adds: “We would like to test if HspBP1 deficient mice will not show aggregated toxic proteins when they also express the disease proteins. Such studies require time and effort and will be our future work.”

For more on neurobiology of Huntington’s disease, see previous coverage. The first author of the paper is graduate student Ting Zhao. The Li lab’s research is supported by the National Institute of Neurological Disorders and Stroke (NS101701, NS036232, NS095279 and NS095181) and the National Natural Science Foundation of China (91332206).

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Posted on by Quinn Eastman in Neuro Leave a comment

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Quinn Eastman

Science Writer, Research Communications qeastma@emory.edu 404-727-7829 Office

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