Mechanisms of DNA double strand break-mediated neurotoxicity in neurodegenerative disease

Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity and long lifespan. DNA double strand breaks (DSBs) are also linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence processes of neuroinflammation and neurodegeneration. Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques. DSB-bearing neurons enter a late-stage DNA damage response marked by NFκB-activated senescent and antiviral immune pathways. In humans, Alzheimer’s disease pathology is significantly associated with immune activation in excitatory neurons. Spatial transcriptomics reveal that regions of CK-p25 brain tissue dense with DSB-bearing neurons harbor signatures of inflammatory microglia, which is ameliorated by NFκB knock down in neurons. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. These findings highlight a novel role for neurons in the mechanism of disease-associated neuroinflammation.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2022

Author dc:creator

• Welch, Gwyneth M.

Advisor dc:contributor.advisor

• Tsai, Li-Huei

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright MIT

Licence dc:rights.uri

• http://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/147534

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/147534