Shawn Ferguson, PhD
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Research Summary
The goal of research in the Ferguson lab is to understand how the status of lysosomes is sensed and how lysosomal function is regulated to meet cellular demands. The basic building blocks (amino acids, sugars, lipids and nucleotides) released by degradation of lysosomal substrates represent important sources of energy during starvation and of material for new macromolecule synthesis to support cell growth and/or remodeling. Conversely, lysosomes are critical for the turnover and clearance from cells of damaged organelles and protein aggregates. The importance of maintaining optimal lysosomal function is demonstrated by contributions of lysosome dysfunction to human neurodevelopmental and neurodegenerative diseases. Furthermore, the role played by lysosomes in sensing cellular energy and nutrient levels and transducing this information into signals controlling growth represents a potential therapeutic target in cancer. With this growing appreciation of the roles played by lysosomes in health and disease, we ultimately seek to address the following fundamental questions:
(A) How do cells sense and regulate the status of their lysosomes?
(B) How does impaired lysosome function contribute to disease states?
(C) How can lysosome function be modulated for therapeutic purposes?
Extensive Research Description
Specific projects under development include:
1. Understanding signaling mechanisms that coordinate lysosomal function (macromolecule degradation) with lysosomal biogenesis. How does a cell match lysosomal capacity with demand? How are signals transduced from the interior of the lysosome to the cytoplasm?
2. Investigation of mechanisms that adapt lysosome function to the unique demands of neurons. In particular, we are highly interested in the mechanisms that support movement of lysosomes over the long distances that are required to provide optimal lysosome function in axons.
3. Investigation of the contributions of lysosome dysfunction to neurodegenerative diseases. We are actively working on projects related to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia as well as a neurodevelopmental disorder arising from mutations in the MAPK8IP3 gene.
4. Determining how macrophages and microglia adapt the function of their lysosomes to support efficient degradation and recycling of materials delivered to them by phagocytosis.
Coauthors
Research Interests
Alzheimer Disease; Axonal Transport; Lysosomes; Parkinson Disease; Tauopathies; TDP-43 Proteinopathies; Frontotemporal Dementia
Research Image
Microtubules in a human neuron
Selected Publications
- Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioningTran M, Tüshaus J, Kim Y, Ramazanov B, Devireddy S, Lichtenthaler S, Ferguson S, Blume J. Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning Traffic 2023, 24: 4-19. PMID: 36398980, PMCID: PMC9825660, DOI: 10.1111/tra.12873.
- ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signalingHancock-Cerutti W, Wu Z, Xu P, Yadavalli N, Leonzino M, Tharkeshwar AK, Ferguson SM, Shadel GS, De Camilli P. ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling Journal Of Cell Biology 2022, 221: e202106046. PMID: 35657605, PMCID: PMC9170524, DOI: 10.1083/jcb.202106046.
- JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeletonRafiq N, Lyons L, Gowrishankar S, De Camilli P, Ferguson S. JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton Communications Biology 2022, 5: 5. PMID: 35013510, PMCID: PMC8748971, DOI: 10.1038/s42003-021-02945-x.
- Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargoDevireddy S, Ferguson SM. Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo Journal Of Cell Biology 2021, 221: e202104044. PMID: 34919127, PMCID: PMC8689666, DOI: 10.1083/jcb.202104044.
- TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanismAlesi N, Akl EW, Khabibullin D, Liu HJ, Nidhiry AS, Garner ER, Filippakis H, Lam HC, Shi W, Viswanathan SR, Morroni M, Ferguson SM, Henske EP. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism Nature Communications 2021, 12: 4245. PMID: 34253722, PMCID: PMC8275687, DOI: 10.1038/s41467-021-24499-6.
- PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s diseaseNackenoff AG, Hohman TJ, Neuner SM, Akers CS, Weitzel NC, Shostak A, Ferguson SM, Mobley B, Bennett DA, Schneider JA, Jefferson AL, Kaczorowski CC, Schrag MS. PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease PLOS Genetics 2021, 17: e1009406. PMID: 33830999, PMCID: PMC8031396, DOI: 10.1371/journal.pgen.1009406.
- PLD3 is a neuronal lysosomal phospholipase D associated with β‐amyloid plaques and cognitive function in Alzheimer’s diseaseNackenoff A, Hohman T, Neuner S, Akers C, Weitzel N, Shostak A, Ferguson S, Bennett D, Schneider J, Jefferson A, Kaczorowski C, Schrag M. PLD3 is a neuronal lysosomal phospholipase D associated with β‐amyloid plaques and cognitive function in Alzheimer’s disease Alzheimer's & Dementia 2020, 16 DOI: 10.1002/alz.043301.
- Dynamin Function in Exocytosis and Endocytosis Coupling of Dense-Core Vesicles in Pancreatic Beta CellsFan F, Wendlick J, Tamarina N, Wu Y, Ferguson S, Philipson L, De Camilli P, Lou X. Dynamin Function in Exocytosis and Endocytosis Coupling of Dense-Core Vesicles in Pancreatic Beta Cells Biophysical Journal 2020, 118: 488a. DOI: 10.1016/j.bpj.2019.11.2700.
- PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvationAmick J, Tharkeshwar AK, Talaia G, Ferguson SM. PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation Journal Of Cell Biology 2019, 219: e201906076. PMID: 31851326, PMCID: PMC7039192, DOI: 10.1083/jcb.201906076.
- Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichmentAngarola B, Ferguson SM. Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment Molecular Biology Of The Cell 2019, 30: 2750-2760. PMID: 31532697, PMCID: PMC6789162, DOI: 10.1091/mbc.e19-03-0146.
- O1‐01‐02: A NOVEL MURINE KNOCK‐IN MODEL FOR PROGRANULIN‐DEFICIENT FRONTOTEMPORAL DEMENTIA WITH NONSENSE‐MEDIATED MRNA DECAYNguyen A, Nguyen T, Zhang J, Devireddy S, Zhou P, Karydas A, Xu X, Miller B, Rigo F, Ferguson S, Huang E, Walther T, Farese R. O1‐01‐02: A NOVEL MURINE KNOCK‐IN MODEL FOR PROGRANULIN‐DEFICIENT FRONTOTEMPORAL DEMENTIA WITH NONSENSE‐MEDIATED MRNA DECAY Alzheimer's & Dementia 2018, 14: p212-p212. DOI: 10.1016/j.jalz.2018.06.2331.
- A Novel Murine Knock‐in Model for Progranulin‐deficient Frontotemporal Dementia with Nonsense‐mediated mRNA DecayNguyen A, Nguyen T, Zhang J, Devireddy S, Zhou P, Karydas A, Xu X, Miller B, Rigo F, Ferguson S, Huang E, Walther T, Farese R. A Novel Murine Knock‐in Model for Progranulin‐deficient Frontotemporal Dementia with Nonsense‐mediated mRNA Decay The FASEB Journal 2018, 32: 807.8-807.8. DOI: 10.1096/fasebj.2018.32.1_supplement.807.8.
- Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathologyGowrishankar S, Wu Y, Ferguson SM. Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology Journal Of Cell Biology 2017, 216: 3291-3305. PMID: 28784610, PMCID: PMC5626538, DOI: 10.1083/jcb.201612148.
- C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signalingAmick J, Roczniak-Ferguson A, Ferguson SM. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling Molecular Biology Of The Cell 2016, 27: 3040-3051. PMID: 27559131, PMCID: PMC5063613, DOI: 10.1091/mbc.e16-01-0003.
- Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaquesGowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: e3699-e3708. PMID: 26124111, PMCID: PMC4507205, DOI: 10.1073/pnas.1510329112.
- Dynamin 2 regulation of integrin endocytosis, but not VEGF signaling, is crucial for developmental angiogenesisLee M, Skoura A, Park E, Landskroner-Eiger S, Jozsef L, Luciano A, Murata T, Pasula S, Dong Y, Bouaouina M, Calderwood D, Ferguson S, De Camilli P, Sessa W. Dynamin 2 regulation of integrin endocytosis, but not VEGF signaling, is crucial for developmental angiogenesis Journal Of Cell Science 2014, 127: e1-e1. DOI: 10.1242/jcs.153080.
- Dynamin 2–dependent endocytosis is required for sustained S1PR1 signalingWillinger T, Ferguson S, Pereira J, De Camilli P, Flavell R. Dynamin 2–dependent endocytosis is required for sustained S1PR1 signaling Journal Of Cell Biology 2014, 204: 2047oia57. DOI: 10.1083/jcb.2047oia57.
- Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPasesPetit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases Journal Of Cell Biology 2013, 202: 1107-1122. PMID: 24081491, PMCID: PMC3787382, DOI: 10.1083/jcb.201307084.
- The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome HomeostasisRoczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM. The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis Science Signaling 2012, 5: ra42. PMID: 22692423, PMCID: PMC3437338, DOI: 10.1126/scisignal.2002790.
- Science Signaling Podcast: 12 June 2012Ferguson S, VanHook A. Science Signaling Podcast: 12 June 2012 Science Signaling 2012, 5 DOI: 10.1126/scisignal.2003263.
- Dynamin 2 regulates S1P1 signalling and T cell migration (173.15)Willinger T, Ferguson S, De Camilli P, Flavell R. Dynamin 2 regulates S1P1 signalling and T cell migration (173.15) The Journal Of Immunology 2012, 188: 173.15-173.15. DOI: 10.4049/jimmunol.188.supp.173.15.
- Coordinated Actions of Actin and BAR Proteins Upstream of Dynamin at Endocytic Clathrin-Coated PitsFerguson S, Raimondi A, Paradise S, Shen H, Mesaki K, Ferguson A, Destaing O, Ko G, Takasaki J, Cremona O, Toole E, De Camilli P. Coordinated Actions of Actin and BAR Proteins Upstream of Dynamin at Endocytic Clathrin-Coated Pits Developmental Cell 2010, 18: 332. DOI: 10.1016/j.devcel.2010.02.003.
- Coordinated Actions of Actin and BAR Proteins Upstream of Dynamin at Endocytic Clathrin-Coated PitsFerguson S, Raimondi A, Paradise S, Shen H, Mesaki K, Ferguson A, Destaing O, Ko G, Takasaki J, Cremona O, Toole E, De Camilli P. Coordinated Actions of Actin and BAR Proteins Upstream of Dynamin at Endocytic Clathrin-Coated Pits Developmental Cell 2009, 17: 811-822. PMID: 20059951, PMCID: PMC2861561, DOI: 10.1016/j.devcel.2009.11.005.
- P2-086 Modeling presynaptic cholinergic hypofunction: pharmacological and behavioral studies in choline transporter heterozygous miceBazalakova M, Ferguson S, Wright J, McDonald M, Blakely R. P2-086 Modeling presynaptic cholinergic hypofunction: pharmacological and behavioral studies in choline transporter heterozygous mice Neurobiology Of Aging 2004, 25: s248. DOI: 10.1016/s0197-4580(04)80833-9.
- Molecular cloning and characterization of hemicholinium-3-sensitive choline transportersApparsundaram S, Ferguson S, Blakely R. Molecular cloning and characterization of hemicholinium-3-sensitive choline transporters Biochemical Society Transactions 2001, 29: a95-a95. DOI: 10.1042/bst029a095a.
- Molecular Cloning of a Human, Hemicholinium-3-Sensitive Choline TransporterApparsundaram S, Ferguson S, George A, Blakely R. Molecular Cloning of a Human, Hemicholinium-3-Sensitive Choline Transporter Biochemical And Biophysical Research Communications 2000, 276: 862-867. PMID: 11027560, DOI: 10.1006/bbrc.2000.3561.