A possible link between neurodegeneration associated aggregates and cellular aging - Prof. Michael Brandeis

Neurodegenerative diseases, like Parkinson and Alzheimer are associated with cellular protein aggregation. A method to follow aggregation in living cultured cells in real time was developed in the laboratory of Prof. Michael Brandeis of the Department of Genetics of the Life Science Institute. This method enables to study the effect of aggregates on cellular proteins and organelles. Ubiquitin is a small protein playing an essential role in protein degradation and DNA damage repair. The omnipresence of ubiquitin in disease associated aggregates is well established. This method enabled, for the first time to characterize the dynamics ubiquitin accumulation on aggregates. Research by the master students Adi Ben Yehuda and Marwa Risheq revealed that this accumulation leads to the depletion of nuclear ubiquitin. Given the role of ubiquitin for DNA repair, this observation suggested that aggregates compromises genome repair. Such a defect is particularly significant in brain neurons that suffer from extensive DNA damage. Ofra Novoplansky, another student in the lab, showed that aggregates puncture the nuclear lamina thereby disrupting the nuclear cytoplasmic compartmentalization. In contrast to most cells in the body, brain neurons hardly regenerate throughout life, their aging is exceedingly slow and their number does hardly decline in old age. Impaired DNA repair, disruption of the nuclear lamina, as well as the reduced capacity to degrade proteins, discovered in a previous research done by this approach, are all well-established hallmarks of aging. The observed correlation between protein aggregation and the appearance of these hallmarks suggests that aggregates cause premature neuron aging and could lead to neurodegeneration. It is important to stress that these are preliminary observations and that their possible application for treating neurodegeneration lay still a far way ahead. This research, published last week in PlosONE, was funded by the Israeli Ministry of Health and the Israeli Science Foundation.

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