CUL5 as a Potential Target to Reduce Tau Levels in the Aging Brain
This is an example of the very earliest stages of research leading to drug discovery, the identification of a potential target protein, here CUL5, that can be manipulated to change cell metabolism in a specific way, here meaning a reduction in the amount of tau protein in the cell. Aggregation of altered tau is a feature of late stage Alzheimer's disease, a cause of cell dysfunction and death in the brain. Reducing tau levels is one possible approach to the problem, though given that tau has a normal and necessary function in the brain, it may not be the best possible approach. At this stage, researchers do not know how CUL5 functions to affect tau levels, and thus a good deal of further work stands between the present discovery and the emergence of any practical outcome.
Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPR interference screen in induced pluripotent stem cell (iPSC)-derived neurons.
In comparison to other tau screens previously reported in the literature, our data have broadly similar patterns of hit genes. A previous genome-wide screen for modifiers of tau levels performed in SHY5Y cells has several shared classes of genetic modifiers. Surprisingly, this screen identified CUL5 as a negative modifier of tau levels. Since CUL5 regulates hundreds of substrates, it is not surprising that CUL5 knockdown has different phenotypes in different contexts.
We find CUL5 expression to be correlated with resilience in tauopathies along with genes encoding CUL5 interactors, including ARIH2 and SOCS4. However, the molecular mechanisms by which CUL5 affects neuronal vulnerability in AD remains to be identified. A broad distribution of CUL5 expression is seen in different neuronal subtypes in the Seattle Alzheimer's Disease Brain Cell Atlas suggesting that CUL5 may modulate disease vulnerability via multiple mechanisms. For instance, it is possible that CUL5 expression affects vulnerability via tau ubiquitination. But, considering CUL5's known role in immune signaling, another possibility is that CUL5 expression affects vulnerability via the neuro-immune axis.