Shawn Ferguson, PhD

Dr. Ferguson's research program defines fundamental mechanisms through which lysosome functions adapt to changes in cellular demand. Building on insights from human genetics and disease pathology, his lab has furthermore identified how dysfunctions in the endolysosomal pathway contribute to neurodegenerative diseases. This intersection between lysosomal biology and neurodegeneration forms a common theme across multiple projects. The Ferguson lab investigates these topics using cutting edge cell biological tools across a range of model systems that spans from mammalian cell lines, human induced pluripotent stem cells that are genome edited and differentiated into macrophages, microglia and neurons, and genetically modified mouse models.

The Ferguson lab identified an mTORC1-dependent regulatory mechanism that coordinates TFEB and related transcription factors, enabling lysosomes to communicate with the nucleus and adjust their function according to cellular needs. The Ferguson team also pioneered findings on the nutrient-regulated recruitment of FLCN-FNIP and C9orf72 (mutated in ALS-FTD) complexes to lysosomes, uncovering new aspects of lysosome biology and critical components linking nutrient sensing to mTORC1 signaling from lysosomes.

Ferguson lab research into lysosomal transport in neuronal axons revealed how disruptions in this process lead to lysosome accumulation within swollen axons around Alzheimer’s disease amyloid plaques. This opened new lines of research into roles played by the JIP3 and JIP4 proteins as scaffold that link lysosomes to motors and signaling proteins. The recent identification of human JIP3 (MAPK8IP3 gene) and JIP4 (SPAG9 gene) mutations as a cause of human neurodevelopmental diseases raised new questions that they are now exploring concerning the role for these proteins and their functions at lysosomes in brain development.

Most recently, the Ferguson lab identified a role for LRRK2 in regulating the lysosomal degradative activity of macrophages and microglia. They also uncovered a novel mechanism that connects the STING pathway signaling, lysosomal damage, LRRK2 signaling, and Parkinson’s disease pathogenesis. In parallel, they identified TBK1, a kinase associated with neurodegenerative diseases (ALS-FTD), as being recruited to lysosomes in response to signals related to innate immunity, nutrient availability, and lysosomal stress. Their research furthermore defined Rab7 as a major substrate that mediates the effects of TBK1 at lysosomes. Most prominently, they found that TBK1-mediated phosphorylation of Rab7 suppresses the inhibitory effect of Rab7 on mTORC1 signaling from lysosomes. Additional important discoveries include identification of roles for prosaposin and Surf4 in the lysosomal delivery of newly synthesized progranulin, whose deficiency causes frontotemporal dementia (FTD) characterized by TDP-43 inclusions. With respect to TDP-43, they have characterized broad effects of TDP-43 depletion on organelle homeostasis that parallel its ability to regulation mRNA splicing via the suppression of cryptic exon inclusion.

These research achievements represent broad contributions to the fields of lysosome cell biology and neurodegenerative disease mechanisms.