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, our knowledge regarding the mechanisms that control lipid delivery remains limited. The long-term goal of our laboratory is to gain mechanistic insights into how cellular lipid compartmentalisation is maintained and understand its role in specializsed cells, particularly neuronal cells.
The Role of Lipids in Neurodegenerative Diseases & Ageing
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 synthesiszed 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. 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 working hypothesis is that lipid regulation at ER-PM contacts is critical for the viability of neurons with particularly long axons, including motor neurons. His lab aims 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.
- EMBO Global Investigator Network (GIN)- Yasunori Saheki
- Functional dissection of membrane contact sites in cellularlipid homeostasis
- Investigating the importance of cholesterol homeostasis for neuronal function
- Understand the molecular mechanisms of aging via functional dissection of cellular lipid homeostasis
- Understanding Dynamic Membrane Contact Sites In Health and Disease
Ercan B*, Naito T*, Koh DHZ, Dharmawan D, and Saheki Y**. (2021). Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b. The EMBO Journal, e106524. *Co-first authors. **Corresponding author.
Naito T, Ercan B, Krshnan L, Triebl A, Koh DHZ, Wei FY, Tomizawa K, Torta F, Wenk MR, and Saheki Y**. (2019). Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex. eLife, pii: e51401. **Corresponding author.
Bian X, Saheki Y**, and De Camilli P**. (2018). Ca2+ releases E-Syt1 autoinhibition to couple ER-plasma membrane tethering with lipid transport. The EMBO Journal, 37:219-234. **Corresponding authors.
Saheki Y**, and De Camilli P**. (2017). Endoplasmic reticulum-plasma membrane contact sites. Annual Review of Biochemistry, 86:659-84. **Corresponding authors.
Dong R, Saheki Y, Swarup S, Lucast L, Harper JW, and De Camilli P. (2016). Endosome-ER contacts control actin nucleation and retromer function through VAP-Dependent Regulation of PI4P. Cell, 166:408-23.
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. Nature Cell Biology, 5:461-3. *Equal contribution.
Fernández-Busnadiego R*, Saheki Y*, and De Camilli P. (2015). Three dimensional architecture of extended synaptotagmin-mediated ER-plasma membrane contact sites. Proceedings of the National Academy of Sciences of the United States of America, 112:4837-8. *Co-first authors.
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. *Equal contribution.
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. *Co-first authors.
Saheki Y, and De Camilli P. (2012). Synaptic vesicle endocytosis. The Synapse, Chapter 5 (79-108). Cold Spring Harbor Lab Press.
Saheki Y, and Bargmann CI. (2009). Presynaptic CaV2 calcium channel traffic requires CALF-1and the alpha (2) delta subunit UNC-36. Nature Neuroscience. 10, 1257-65. News and Views in Nat Neurosci. 10, 1213-4 (2009).
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 Research, 1055:196-201.