Tauopathies, including Alzheimer’s disease and frontotemporal dementia, rank among the most prevalent age-related neurodegenerative disorders, characterized by the progressive accumulation
and aggregation of the microtubule-associated protein tau in vulnerable neuronal subtypes. Despite decades of research, the molecular mechanisms dictating why certain neurons accumulate toxic tau aggregates while others remain resilient have remained elusive. A new study published in Cell by BARI member Martin Kampmann and his team tackles this challenge head-on by conducting a genome-wide CRISPR interference (CRISPRi) screen in human induced pluripotent stem cell (iPSC)-derived neurons, systematically identifying cellular factors that control tau oligomer levels (which represent the earliest steps in tau aggregation) and proteostasis. This unbiased approach uncovered both established and novel pathways, offering fresh insights into cell-type-specific vulnerability and potential therapeutic entry points for these devastating, age-linked diseases.
A systematic CRISPRi screen in human neurons
The Kampmann team engineered iPSC-derived neurons to express CRISPRi machinery to enable a genome-wide screen to knock down thousands of genes and monitor effects on tau oligomer accumulation. This neuronal model recapitulates key aspects of human tau biology, allowing the identification of hits that modulate tau levels under physiological and stress conditions. Among the top findings were unexpected regulators, including components of the UFMylation pathway (a ubiquitin-like modification system) and GPI anchor biosynthesis, which influence tau oligomerization and stability. A standout discovery was the E3 ubiquitin ligase complex CRL5SOCS4, which directly ubiquitinates tau, promotes its degradation, and controls its steady-state levels in human neurons. Notably, higher expression or activity of CRL5SOCS4 correlates with resilience to tau pathology in human postmortem brain data from tauopathy patients, suggesting it acts as a protective factor against disease progression.
Linking mitochondrial dysfunction to tau pathology
The screen also revealed connections between mitochondrial function and tau proteostasis. Disruption of mitochondrial pathways led to proteosomal misprocessing of tau, generating disease-relevant proteolytic fragments, truncated tau species known to seed aggregation and spread in tauopathies. These fragments altered tau aggregation dynamics in vitro, providing a mechanistic link between mitochondrial impairment (a hallmark of aging and neurodegeneration) and the production of pathogenic tau conformers.
Together, these results highlight how perturbations in energy metabolism can exacerbate tau toxicity, reinforcing the idea that cellular stress responses intersect with protein quality control to determine neuronal fate in aging brains.
Why this matters for age-related neurodegeneration
This study advances the field by providing a comprehensive map of tau proteostasis regulators in human neurons, moving beyond rodent models or non-neuronal cells to capture human-specific biology. Tauopathies remain incurable with no disease-modifying therapies available, largely due to incomplete understanding of selective vulnerability. By identifying pathways like UFMylation, GPI anchoring, and CRL5SOCS4-mediated ubiquitination, the work identifies druggable targets that could enhance tau clearance, prevent fragment formation, or bolster resilience in at-risk neurons.
What’s next for the Kampmann lab?
To understand more deeply how the aging brain environment enables neurodegenerative disease, the Kampmann lab recently developed a platform enabling highly scalable in vivo CRISPR screens in mouse brains and is applying this approach to uncover mechanisms that either drive vulnerability or resilience of neurons in vivo. A major focus is also on the mechanisms driving synapse loss – an early event in neurodegeneration that highly correlates with cognitive decline. Using novel technologies, the lab is aiming to uncover mechanisms in both neurons and non-neuronal brain cells such as microglia and astrocytes that control synapse loss.