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Kampmann group publishes a paper in Nature Neuroscience detailing their work ito identify the molecular signature of neurons selectively to Alzheimer’s disease

A hallmark of neurodegenerative diseases is that specific neurons are vulnerable, whereas others are resilient. While selectively vulnerable neurons are well-characterized for Parkinson’s disease and ALS, much less is known about those neurons most vulnerable to Alzheimer’s disease, the most common neurodegenerative disease.

In a study published today in Nature Neuroscience, the Kampmann lab at the IND collaborated with Dr. Lea Grinberg’s lab at the UCSF Memory and Aging Center to identify the molecular signature of neurons selectively to Alzheimer’s disease. Kampmann lab students Kun Leng and Emmy Li led the project and used single-nucleus RNA sequencing in postmortem human brain samples to uncover neuron populations that accumulate tau pathology and die early in disease.

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CRISPRi Screen Discovers Mitochondrial Distress Signal

The function of mitochondria, the “powerhouse of the cell,” can be compromised in aging and disease. Dysfunctional mitochondria trigger a global cellular stress response, but how human mitochondria signal stress to the rest of the cell was unknown.

In a project led by postdoc Xiaoyan Guo in the Kampmann lab, a CRISPRi-based genetic screen uncovered the molecular mechanism by which mitochondrial dysfunction is relayed to the rest of the cell. The mitochondrial protease OMA1 cleaves a previously little characterized protein, DELE1. Cleaved DELE1 activates the kinase, HRI, triggering the so-called integrated stress response.

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Spreading of tau aggregates between cells is thought to be an important mechanism by which Alzheimer’s disease and several other neurodegenerative diseases progress. A major question is which cellular pathways mediate or counteract this process.

In a project led by postdoc John Chen in the Kampmann lab, a CRISPR-based genetic screen revealed an important role for the ESCRT pathway to prevent the escape of internalized tau aggregates from the endolysosomal pathway into the cytosol, where they can seed more tau aggregation. Collaborators included the Gestwicki and Southworth labs at the IND, the Grinberg lab at UCSF, and the Leonetti lab at the Chan Zuckerberg Biohub.

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