Scientists uncover why some brain cells resist Alzheimer's disease and they identified a key player

Good news!

"Key takeaways

• Tau is the most common protein that aggregates in neurodegeneration diseases. However, researchers had not determined why some types of neurons are affected more than others.
• The work identified a protein complex called CRL5SOCS4 that marks tau for degradation. The findings suggest that strengthening this natural defense mechanism could represent a new therapeutic strategy for neurodegenerative diseases.
• Enhancing CRL5SOCS4 activity could help neurons clear tau more effectively, while strategies to maintain proteasome function during stress might prevent the formation of toxic tau fragments.

...

uncovered why certain brain cells are more resilient than others to the buildup of a toxic protein that is a hallmark of Alzheimer’s disease and related dementias ...

used a novel CRISPR-based genetic screening approach on lab-grown human brain cells to determine the cellular machinery that controls the accumulation of tau protein in the brain. ...

Among more than 1,000 genes identified, the CRL5SOCS4 protein complex emerged as a key player that attaches molecular tags to tau, marking it for destruction by the cell’s recycling machinery.

Importantly, analysis of brain tissue from Alzheimer’s patients revealed that higher expression of CRL5SOCS4 components made neurons more likely to survive despite the accumulation of tau protein. 

The study also revealed an unexpected connection between mitochondrial dysfunction and tau toxicity. When the researchers disrupted the cellular powerhouses that generate energy, they triggered the production of a specific tau fragment approximately 25 kilodaltons in size. This fragment closely resembles a biomarker found in the blood and spinal fluid of Alzheimer’s patients, known as NTA-tau. ..."

From the highlights and abstract:

"Highlights

• CRISPR screens in human neurons reveal modifiers of tau oligomer accumulation

• CUL5 and the substrate-specific adaptor SOCS4 function as tau E3 ubiquitin ligase

• Expression of CUL5 complexes is correlated with resilience in tauopathies

• Reactive oxygen species generate a disease-relevant tau proteolytic fragment

Summary

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 CRISPRi screen in induced pluripotent stem cell (iPSC)-derived neurons. The screen uncovered both known and unexpected pathways, including UFMylation and GPI anchor biosynthesis, which control tau oligomer levels. We discovered that the E3 ubiquitin ligase CRL5SOCS4 controls tau levels in human neurons, ubiquitinates tau, and is correlated with resilience to tauopathies in human disease. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, generating disease-relevant tau proteolytic fragments and changing tau aggregation in vitro. These results systematically reveal principles of tau proteostasis in human neurons and suggest potential therapeutic targets for tauopathies."

Scientists uncover why some brain cells resist Alzheimer's disease | UCLA "Study identifies cellular defense system that protects neurons from toxic tau proteins, opening door to new treatments"

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis (open access)

Graphical abstract