Aggregates may help neurons cope with toxic protein forms
Multiple major neurodegenerative diseases involve the formation of protein aggregates which are prime suspects in the damage and cell death associated with these diseases. A key, yet unresolved question regarding such aggregates is their causative nature: Are they directly damaging (and hence targets for therapeutic elimination)? Or, perhaps, a protective coping mechanism, which reduces the damage of toxic proteins by sequestering them into relatively harmless deposits?
One such disease is Huntington’s disease (HD), a progressive, incurable neurodegenerative disorder, caused by abnormal, toxic forms of the protein huntingtin. In a recent study led by the graduate student Ayub Boulos from the Rappaport Faculty of Medicine, advanced imaging techniques were used to track the fate of mutated huntingtin over several weeks in neurons in culture. The study demonstrated that the mutated protein accumulates into large aggregates formed primarily in remote axons, far from the sensitive cell body and nucleus. This dramatically reduced levels of the toxic protein in the rest of the cell, which remained viable over these long observation periods.
What happens if aggregation is suppressed? In a prior study from the same groups, huntingtin in the brains of HD animal models was found to be specifically modified (ubiquitinated) in manners that promoted aggregate formation; moreover, preventing these modifications led to less large aggregates and numerous, particularly harmful tiny ones. Indeed, in the current study, in neurons in which ubiquitination of mutated huntingtin was precluded, sequestration in remote locations was less effective, large aggregates appeared in cell nuclei and neuron death was widespread.
"Our results lend support to the notion that aggregates can help neurons to cope, at least temporarily, with the potential damage of toxic proteins, and by doing so, delay the damage and cell death caused by such proteins” noted the senior authors, Prof. Aaron Ciechanover and Prof. Noam Ziv from the Rappaport Faculty of Medicine. Whether this applies to other neurodegenerative disorders remains to be seen, but imaging platforms similar to the one used here, should prove useful in this respect.
The study was published in Communications Biology on August 18, 2024
