Assistant Professor Yasunori Saheki

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Nanyang ​Assistant Professor Yasunori Saheki
MD, PhD
Principal Investigator, Cell Biology ​and Molecular Neuroscience Laboratory
Lab website: www.thesahekilab.com

 
 
Introduction
Assistant Professor Yasunori Saheki is a Nanyang Assistant Professor at Lee Kong Chian School of Medicine, Nanyang Technological University.

Asst Prof Saheki attended Okayama University Medical School in Okayama, Japan, obtaining his MD in 2005. He then enrolled in David Rockefeller Graduate Program at the Rockefeller University in New York, USA. Working in the laboratory of Dr. Cori Bargmann, he investigated the mechanisms of ion channel localisation at the nerve terminals using C. elegans. After receiving his PhD in Neurobiology in 2010, Asst Prof Saheki moved to the Department of Cell Biology at the Yale University School of Medicine in New Haven, where he worked as a postdoctoral fellow in the laboratory of Dr. Pietro De Camilli, supported by fellowships from the Uehara memorial foundation and the Japan Society for the Promotion of Science. Using a combination of genome editing, biochemistry, quantitative cellular imaging, and optogenetics, he studied the regulatory mechanisms that govern cellular lipid homeostasis. He joined the faculty at Lee Kong Chian School of Medicine as a Nanyang Assistant Professor in March, 2016. His laboratory employs the combination of C. elegans genetics and mammalian cell biology to tackle fundamental questions in cellular lipid regulation as well as the mechanisms that underlie neurological disorders.


Research Focus

Lipid homeostasis plays a central role in membrane integrity, signalling and cell viability in all eukaryotic cells. Dynamic transfer of lipids from one cellular compartment to another functions in this process; however, knowledge regarding the mechanisms that control lipid delivery remains limited. The long-term goal of the laboratory is to gain mechanistic insights into how cellular lipid compartmentalisation is maintained and understand its role in specialised cells, particularly neuronal cells. 

Lipid regulation at membrane contact sites
In eukaryote, most membrane lipids are synthesised in the endoplasmic reticulum (ER). Vesicular transport, which employs membrane budding and fusion reactions, plays an important role in delivery of newly synthesised lipids to other membranes. However, growing evidence suggests a critical role of non-vesicular transport in lipid exchange at membrane contact sites between the ER and other membranous organelles as well as the plasma membrane (PM). Asst Prof Saheki’s lab aim to uncover the function of membrane contact sites, with particular focus on ER-PM contacts, in order to advance our knowledge in lipid homeostasis.
Lipid homeostasis in neuronal cells

Neuronal cells extend multiple processes for efficient neurotransmission; synaptic membranes are highly dynamic and can be separated from the cell body by a significant distance. At distant nerve terminals, vesicular transport is not sufficiently rapid to replenish the loss of PM lipids. Neuronal processes, including axons and dendrites, are highly decorated with a continuous network of the ER (Figure1). Therefore, non-vesicular lipid transport via ER-PM contacts is likely to have significant roles in maintenance of the neuronal PM. Significantly, mutations in ER morphogenetic proteins have been identified in neurodegenerative disorders including motor neuron diseases. Asst Prof Saheki’s laboratory working hypothesis is that lipid regulation at ER-PM contacts is critical for the viability of neurons with particularly long axons, including motor neurons. They aim to elucidate the basic principle of lipid homeostasis in neuronal cells and uncover the mechanisms of the progression of neurodegeneration.

Links to neurodegeneration
The potential role of membrane contact sites in lipid exchange is fundamental for our understanding of lipid homeostasis, and these results have broad implications. Moreover, recent human genetic studies revealed the strong link between motor neuron diseases with more common neurodegenerative disorders including Parkinson’s disease, and Alzheimer’s disease. Therefore, the study of motor neuron diseases, and more generally the mechanisms of lipid regulation, may advance our understanding of other neurodegenerative disorders.
 
Figure 1. Maintenance and regulation of the neuronal plasma membrane.
(A) The ER extends throughout the neuronal processes and forms physical contacts with the PM. These ER-PM contacts are implicated in lipid transfer, signalling, Ca2+ homeostasis and synaptic plasticity. Red arrows indicate classical vesicular transport via Golgi apparatus, which is absent in neuronal processes. (B) An electron micrograph showing ER-PM contacts at a dendritic spine. Adapted from Synapse Web by Kristen M. Harris.
 

 LKCMedicine Research Spotlight

 
 

Key Public​ations
  1. Saheki Y* and De Camilli P* (2017). Endoplasmic reticulum-plasma membrane contact sites. Annu Rev Biochem. 86, 659-684 *Co-corresponding authors
  2. Dong R, Saheki Y, Swarup S, Lucast L, Harper JW, De Camilli P (2016). Endosome-ER contacts control actin nucleation and retromer function through VAP-Dependent Regulation of PI4P. Cell. 166, 408-423
  3. Saheki Y, Bian X*, Schauder CM*, Sawaki Y, Surma MA, Klose C, Pincet F, Reinisch KM, and De Camilli P (2016). Control of plasma membrane lipid homeostasis by the extended synaptotagmins. Nat Cell Biol. 5, 504-15. News and Views in Nat Cell Biol. 5, 461-3 (2016). Recommended in Faculty 1000. *Equal contribution
  4. Fernández-Busnadiego R*, Saheki Y*, and De Camilli P (2015). Three dimensional architecture of extended synaptotagmin-mediated ER-plasma membrane contact sites. Proc Natl Acad Sci U S A. 112(16): E2004-13. Commentary in Proc Natl Acad Sci U S A, 112(16):4837-8 (2015). *Co-first authors
  5. Schauder CM, Wu X*, Saheki Y*, Narayanaswamy P, Torta F, Wenk MR, De Camilli P, and Reinisch KM (2014). Structure of a lipid-bound extended-synaptotagmin indicates a role in lipid transfer. Nature. 510, 552-5. Recommended in Faculty 1000. *Equal contribution
  6. Giordano F*, Saheki Y*,  Idevall-Hagren O, Colombo S, Pirruccello M, Milosevic I, Gracheva EO, Sviatoslav BN, Borgese N, and De Camilli P (2013). PI(4,5)P2 dependent and Ca2+-regulated ER-plasma membrane interactions mediated by the extended synaptotagmins. Cell. 153, 1494-509. Preview in Cell, 153, 1423-1424 (2013). Recommended in Faculty 1000. *Co-first authors
  7. Saheki Y and De Camilli P: The Synapse, Chapter 5 (79-108): Synaptic vesicle endocytosis (2012). Cold Spring Harbor Lab Press. Cover article
  8. Saheki Y and Bargmann CI (2009). Presynaptic CaV2 calcium channel traffic requires CALF-1 and the alpha (2) delta subunit UNC-36. Nat Neurosci. 10, 1257-65. News and Views in Nat Neurosci. 10, 1213-4 (2009). Recommended in Faculty 1000
  9. Bauer Huang SL, Saheki Y, VanHoven MK, Torayama I, Ishihara T, Katsura I, van der Linden A, Sengupta P, and Bargmann CI (2007). Left-right olfactory asymmetry results from antagonistic functions of voltage-activated calcium channels and the Raw repeat protein OLRN-1 in C. elegansNeural Dev. 2, 24
  10. Saheki Y, Li ST, Matsushita M, Wu YM, Cai WH, Wei FY, Lu YF, Moriwaki A, Tomizawa K, and Matsui H (2005). A new approach to inhibiting astrocytic IP3-induced intracellular calcium increase in an astrocyte-neuron co-culture system. Brain Res. 1055, 196-201