QUANTITATIVE CELLULAR AND MOLECULAR IMAGING, CELLULAR DYNAMICS & LIPID DROPLET BIOLOGY
Lipid metabolism and membrane assembly in yeast and mammals; yeast as a model of lipid-associated disorders; implementation of advanced imaging and image processing methods to investigate membrane and organelle structure, dynamics and interactions; quantitative microscopy, 4D-live cell imaging, photoconvertible fusion proteins, extended-resolution (deconvolution) and superresolution microscopy (N-STORM); non-linear optical imaging (CARS, SHG, 2-photon microscopy); light-sheet microscopy & optical clearing.
Role of BSCL2/seipin in phosphatidic acid homeostasis
Berardinelli–Seip congenital lipodystrophy type 2 gene (BSCL2) encodes the protein BSCL2 (“seipin”). Loss-of-function mutations in BSCL2 are associated with congenital generalized lipodystrophy type 2 (CGL-type 2), the most severe genetic lipodystrophy disease in humans leading to an almost complete absence of adipose tissue (Ref). CGL-type 2 is unhealable. Therapeutic options are limited to the treatment of occurring metabolic syndromes. Seipin function is studied for decades in different cell systems including the yeast Saccharomyces cerevisiae. However, the specific molecular function(s) of seipin and its role in the pathogenesis of CGL-type 2 is still elusive and controversially discussed.
At the cellular level, seipin malfunction affects both neutral lipid and glycerophospholipid metabolism exemplified in yeast, mice, other model systems and human cells by multiple abnormal cellular phenotypes such as aberrant formation and assembly of neutral lipids stores, altered phospholipid membrane synthesis and distribution, or aberrant ER and mitochondrial calcium homeostasis.
We hypothesize that seipin functions as a lipid-binding protein in particular for membrane-affecting phosphatidic acid, besides its role in LD assembly. Lack of seipin leads to locally elavated PA levels at LD-ER contacts sites and at an LD-forming subdomain of the nER, causing different abnormal cellular phenotypes.
Using advanced optical imaging technologies and methods available at the IMB-Graz (Optical Imaging Resource) we follow this thread and aim at differentiating direct from indirect spatio-temporal effects caused by seipin malfunction to uncover the trigger(s) causing the disease in humans.
Pribasnig, M., Kien B., Pusch L., Haemmerle G., Zimmermann, R. & Wolinski H*. Extended-resolution confocal imaging of the interaction between lipid droplets and mitochondria. (2018). BBA Molecular and Cell Biology of Lipids, 1863(10):1285-1296.
H. Wolinski* (*corresponding author), H.F. Hofbauer, K. Hellauer, A. Cristobal-Sarramian, D. Kolb, M. Radulovic, O.L. Knittelfelder, G.N. Rechberger, S.D. Kohlwein (2015). Seipin is involved in the regulation of phosphatidic acid metabolism at a subdomain of the nuclear envelope in yeast. BBA Molecular and Cell Biology of Lipids 1851 (11):1450-1464.
Paar, M., Jüngst, C., Steiner, N.A., Magnes, C., Sinner, F., Kolb, D., Lass, A., Zimmermann, R., Zumbusch, A., Kohlwein, S.D., & Wolinski, H. Remodeling of lipid droplets during lipolysis and growth in adipocytes (2012) Journal of Biological Chemistry, 287 (14), pp. 11164-11173.
Heimo WolinskiSenior Scientist
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