Many common neurodegenerative diseases, including Alzheimer’s Disease, Parkinson’s Disease, ALS (Lou Gehrig disease) and frontotemporal dementia are associated with aggregation of specific proteins in the brain. Recent evidence shows that these aggregates behave as prions and spread across cell boundaries during disease progression. However, we lack an understanding of the mechanisms driving these processes and the downstream effects on neuronal function.
We hypothesize that specific proteostasis factors control formation, spread and clearance of protein aggregates associated with neurodegenerative diseases. Using our functional genomics approach in human iPSC-derived neurons, we aim to identify these factors to shed light on the cellular mechanisms underlying neurodegenerative diseases, and to identify potential therapeutic targets. In collaboration with colleagues at the IND, we combine several cutting-edge technologies to discover and develop effective drugs for neurodegenerative diseases.
Transcriptomics/proteomics of vulnerable and resilient neurons detects differentially expressed genes but does not reveal those functionally relevant for selective vulnerability. CRISPR-based screens can elucidate determinants of vulnerability, which are potential therapeutic targets. We are implementing CRISPRi and CRISPRa genetic modifier screens in cell types (neurons, glia) and brain organoids derived from patient iPSCs and isogenic controls to reveal disease mechanisms and therapeutic targets.
Our research on neurodegenerative diseases is funded by the Paul G. Allen Family Foundation (Allen Distinguished Investigator Award), the Alzheimer's Association, the National Institutes of Neurological Disorders and Stroke / National Institutes of Health, the Tau Consortium, the California Institute for Quantitative Biomedical Research / Calico Longevity Award and the Glenn Foundation for Medical Research.
- Kampmann M (2017) A CRISPR Approach to Neurodegenerative Diseases. Trends in Molecular Medicine 23:483-485. PMID 28478951.