ABOUT THE RESEARCHER

OVERVIEW

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The rotation of the Earth subjects terrestrial organisms to daily light/dark cycles. To keep in sync with these geophysical oscillations, we have evolved a biological timing system that segregates our behavior, physiology, and metabolism with circadian – or nearly 24 hour (from circa diem, ‘about a day’) – rhythmicity. The circadian timekeeping system is a prediction mechanism that synchronizes internal organismal state with the external environment. While the central clock resides in the brain, all our cells have circadian clocks. Disruption of circadian rhythms is extraordinarily common in modern society and has been linked with neurological disease, metabolic disease, cancer, and aging.

Our research seeks to understand the fundamental relationships between the circadian clock and diseases of the developing brain. We have identified the core circadian clock protein BMAL1 as a regulator of protein synthesis (i.e. translation) (Cell, 2015). BMAL1 promotes circadian rhythms in protein synthesis as a substrate of the mechanistic target of rapamycin (mTOR) pathway, a critical gauge of nutritive status and stress. We have characterized a novel, potentially modifiable link between the circadian timing system and cellular signaling.

One of our major goals is the identification of the mechanisms of circadian-regulated protein synthesis in neural and non-neural cells. How are rhythms of protein synthesis generated? How does protein synthesis coordinate circadian timekeeping? What is the signaling logic that dictates which proteins are made at which time of day? How do circadian rhythms affect protein synthesis in neurons? How do circadian clocks in the brain impact neural function? How are these mechanisms disrupted in neurological disease models?

We utilize and develop animal models, cell-based reporter assays, live cell imaging, behavioral assays, and biochemistry to address fundamental questions of circadian timing, translation, and neurological function with our gaze focused on diseases of the nervous system.

BACKGROUND

Slight modifications: Jonathan Lipton received his MD and PhD degrees from the Albert Einstein College of Medicine, performing graduate work with Scott Emmons studying the genetics of motivational behavior. After a residency and chief residency in Child Neurology and fellowship in Sleep Medicine at Boston Children’s Hospital and Harvard Medical School, he completed post-doctoral studies with Mustafa Sahin, investigating circadian rhythm dysfunction in models of neurodevelopmental disease. He has received research support from the Howard Hughes Medical Institute, Shore Foundation, Tuberous Sclerosis Alliance, Hearst Foundation, American Academy of Neurology, American Sleep Medicine Foundation, the DoD, and the NIH and was the recipient of the Sleep Research Society's Young Investigator Award.

PUBLICATIONS

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  1. Persistent CO2 reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice. J Cereb Blood Flow Metab. 2021 Jul 06; 271678X211021771. View abstract
  2. Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking. Hum Mol Genet. 2020 01 15; 29(2):320-334. View abstract
  3. Mechanisms of sleep and circadian ontogeny through the lens of neurodevelopmental disorders. Neurobiol Learn Mem. 2019 04; 160:160-172. View abstract
  4. Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups. Cancer Cell. 2018 09 10; 34(3):396-410.e8. View abstract
  5. mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex. Neuropsychopharmacology. 2018 05; 43(6):1457-1465. View abstract
  6. Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. Cell Rep. 2017 07 25; 20(4):868-880. View abstract
  7. Neural Circuitry of Wakefulness and Sleep. Neuron. 2017 Feb 22; 93(4):747-765. View abstract
  8. Impaired Mitochondrial Dynamics And Mitophagy In Neuronal Models Of Tuberous Sclerosis Complex. Cell Rep. 2016 11 15; 17(8):2162. View abstract
  9. Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. Cell Rep. 2016 10 18; 17(4):1053-1070. View abstract
  10. Direct current stimulation induces mGluR5-dependent neocortical plasticity. Ann Neurol. 2016 08; 80(2):233-46. View abstract
  11. The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation. Cell. 2015 May 21; 161(5):1138-1151. View abstract
  12. The neurology of mTOR. Neuron. 2014 Oct 22; 84(2):275-91. View abstract
  13. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014 Jun; 75(6):943-58. View abstract
  14. Fragile X syndrome therapeutics: translation, meet translational medicine. Neuron. 2013 Jan 23; 77(2):212-3. View abstract
  15. 16p11.2-related paroxysmal kinesigenic dyskinesia and dopa-responsive parkinsonism in a child. Neurology. 2009 Aug 11; 73(6):479-80. View abstract
  16. Melatonin deficiency and disrupted circadian rhythms in pediatric survivors of craniopharyngioma. Neurology. 2009 Jul 28; 73(4):323-5. View abstract
  17. Insomnia of childhood. Curr Opin Pediatr. 2008 Dec; 20(6):641-9. View abstract
  18. CNS relapse of acute myelogenous leukemia masquerading as pseudotumor cerebri. Pediatr Neurol. 2008 Nov; 39(5):355-7. View abstract
  19. Kawasaki disease: cerebrovascular and neurologic complication. Uncommon Causes of Stroke. 2008. View abstract
  20. Kawasaki disease: cerebrovascular and neurologic complications. Uncommon Causes of Stroke (editor LR Caplan). 2008. View abstract
  21. Disruption of Circadian Melatonin Secretion in Pediatric Craniopharyngioma Survivors with Hypersomnolence. Sleep (Abstract). 2008. View abstract
  22. Mating worms and the cystic kidney: C. elegans as a model for renal disease. Pediatric Nephrology. 2005; 20:1531-36. View abstract
  23. Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple in vertebrate. Journal of Neuroscience. 2004; 24:7427-34. View abstract
  24. The genetic basis of male mating behavior. Journal of Neurobiology. 2003; 54:93-110. View abstract
  25. Genetics of Sexually Motivated Behavior in Caenorhabditis elegans. 2003. View abstract