CRISPR screening in human neurons reveals new insights into Alzheimer’s disease.

CRISPR genome-wide screening identifies protein complex CRL5-SOCS4, providing new insights for Alzheimer's disease research

In neurodegenerative disorders such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), the abnormal aggregation of the tau protein is considered a key driver of neuronal death.

Yet one persistent question remains: under the same pathological conditions, why do some neurons accumulate large amounts of tau protein and rapidly degenerate, while others exhibit greater resilience?

Recently, research teams from the University of California, Los Angeles (UCLA) and the University of California, San Francisco (UCSF) published a study in the journal Cell, systematically elucidating the regulatory mechanisms underlying tau protein accumulation in human neurons.

CRISPR Genome-Wide Screening for Initial Identification

The researchers used human neurons differentiated from iPSCs and introduced the CRISPR interference (CRISPRi) gene-editing system to individually suppress nearly every gene in the human genome.

This approach enabled a systematic evaluation of how the perturbation of each gene affects tau protein accumulation.

Unlike traditional strategies that rely on animal models or candidate-gene hypotheses, this unbiased genome-wide screening approach allowed investigators to capture both known pathways and previously unrecognized regulatory mechanisms simultaneously, while more closely reflecting the molecular context of human disease.

Key Finding: The CRL5-SOCS4 Complex and Tau Clearance

Among the more than 1,000 genes identified as regulators of tau homeostasis, a protein complex known as CRL5-SOCS4 stood out. The study shows that this complex promotes proteasomal degradation of tau by attaching ubiquitin tags to the protein.

In vitro experiments confirmed that recombinant CRL5-SOCS4 — composed of CUL5, SOCS4, ELOB/ELOC, and ARIH2 — can directly ubiquitinate tau. Deletion of CUL5 or SOCS4 led to a marked increase in total tau levels and tau oligomers, predominantly accumulating in the neuronal soma.

Further analyses revealed that in patients with AD, FTD, and related disorders, higher expression of CRL5-SOCS4 components, such as CUL5, positively correlates with the survival of resilient neuronal populations, whereas expression is reduced in more vulnerable neurons.

These findings suggest that enhancing the activity of this complex may strengthen the neurons’ intrinsic protective mechanisms.

The researchers propose that boosting this endogenous defense pathway could offer a new therapeutic direction for tau-associated neurodegenerative diseases.

Unexpected Discovery:
Mitochondrial Stress and the Formation of Aberrant Tau Fragments

Beyond protein degradation pathways, the study uncovered a previously underappreciated link between tau toxicity and mitochondrial dysfunction.

When mitochondrial function was disrupted in neurons, the cells generated a tau fragment of approximately 25 kDa. This fragment closely resembles NTA-tau, a biomarker previously detected in the blood and cerebrospinal fluid of patients with Alzheimer’s disease, in both structure and characteristics.

The findings further indicate that under conditions of oxidative stress, impaired proteasome activity may lead to abnormal processing of tau, resulting in more toxic aggregated species.

In vitro data showed that this aberrant tau fragment can alter the pattern of tau aggregation, suggesting that it may contribute to disease progression.

Conclusion

“We set out to understand why some neurons are particularly vulnerable to tau accumulation, while others appear more resistant,” said Dr. Avi Samelson, Assistant Professor of Neurology at UCLA and first author of the study.

“By screening nearly the entire human genome, we were able not only to confirm expected pathways, but also to uncover entirely new mechanisms, such as UFMylation and GPI anchoring, that had not previously been linked to tau homeostasis.”

The researchers emphasize that these findings remain at the basic research stage and will require further validation before any clinical translation. Nonetheless, the results provide important insights into the differential vulnerability of neuronal populations and offer potential new targets for therapeutic intervention.

Looking ahead, the deeper integration of CRISPR technologies with human cell–based models is expected to usher in a more systematic and refined phase in deciphering the complex mechanisms underlying neurodegenerative diseases.

References

1. Samelson AJ, et al. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. Cell. 2026 Jan 28.
2. Scientists uncover why some brain cells resist Alzheimer's disease. UCLA Health News. 2026 Jan 29.
3. This Cellular Hazmat Team Cleans Up Tau. Can It Prevent Dementia? UCSF News. 2026 Jan 29.
4. A Hidden Cellular Defense May Protect the Brain From Alzheimer's. SciTechDaily. 2026 Feb 2.