Sarah Cohen

Awesome paper and super useful resource of CRISPR-based screens to identify regulators of #LipidDroplet biology under different metabolic conditions: crisprlipid.org

CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly - Nature CRISPR–Cas9 screening identifies CLCC1 as a factor that increases neutral lipid flux to prevent hepatic steatosis and promotes nuclear pore complex assembly by promoting membrane bending and fusi...

Sooo happy to share our new paper in @nature.com “CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.” A terrific collaboration with @arrudalab.bsky.social, led by co–first authors Alyssa Mathiowetz and Emily Maymand.
www.nature.com/articles/s41...

Wow, congratulations Prasanna!! So well deserved. 🥂🎉

Thrilled to share that the first part of my PhD work from @cohenlaboratory.bsky.social lab is now on bioRxiv! www.biorxiv.org/content/10.6... Check out the threads below:

Thanks Rachid! 🙏

Thank you, Bianca!

Thanks for your kind words, Andre!

Thank you, Toni!

bsky.app/profile/cohe...

I'm delighted to present TWO new preprints from my lab, led by @mczanellati.bsky.social and @sherryhsu.bsky.social, about how #organelles remodel throughout #NeuronalDifferentiation. Check out the threads about their papers below:

Thank you to all the co-authors – this was a wonderful collaboration with the lab of Mohanish Deshumukh. Thank you also to Wendy Salmon for expert microscopy advice, and to
NIGMS, @chanzuckerberg.bsky.social, and @allenphilanthro.bsky.social for funding! 13/13

A huge thank you to all co-authors, WendySalmon (UNC Hooker Imaging Core) for expert microscopy advice, and NIH
and @chanzuckerberg.bsky.social for funding!!

Our data support a model in which tubulin acetylation coordinates lysosome-ER interactions to facilitate lysosome remodeling. This work establishes tubulin acetylation as a key cytoskeletal regulator important for neuronal differentiation. 9/9

Finally, we asked whether the observed morphological changes were coupled to functional changes. Loss of acetylated microtubules leads to enlarged, highly acidified lysosomes, and accumulation of autolysosomes, consistent with defective lysosomal reformation. 8/9

We also looked at lysosome dynamics and maturation. We found tubulin acetylation governs lysosome dynamics by supporting normal fission frequency. 7/9

One of the top hits we found was altered lysosome-endoplasmic reticulum (ER) contact. Super-resolution microscopy reveals that lysosome-ER contacts preferentially associate with acetylated microtubules in iNeurons. 6/9

Leveraging our quantitative analysis pipeline github.com/SCohenLab/in..., we systematically profiled organelles in iNeurons. Loss of tubulin acetylation broadly alters organelle morphology, distribution, and interactions, with #lysosome-organelle interactions most affected. 5/9

Does tubulin acetylation dictate organelle behavior? We used quantitative multispectral imaging to simultaneously profile 8 membrane-bound organelles and decipher how tubulin acetylation shapes organelle architecture and interaction networks during neuronal differentiation. 4/9

Are these PTMs spatially patterned? We saw that they are spatially organized. Remarkably, a perinuclear population of acetylated tubulin progressively accumulates during neuronal differentiation. 3/9

Led by @sherryhsu.bsky.social, we began by profiling 3 tubulin post-translational modifications (PTMs) - acetylation, polyglutamylation, and detyrosination - during neuronal differentiation. In iPSC-derived neurons, we see dramatic enrichment of all 3 PTMs during differentiation. 2/9

During #NeuronalDifferentiation, #organelles dramatically reorganize. #Microtubules are essential tracks for transport. But are they just highways, or can they instruct organelle behavior? Are tubulin modifications a regulatory code that guides organelle position or function? 1/9

Overall, we observed extensive remodeling of the organelle interactome as iPSCs differentiate into neurons, characterized by an initial metabolic shift, followed by lipid remodeling. This rewiring establishes a neuron-specific network required to support neuronal function. 12/13

Excitingly, reduction in ether lipids by VAPB/ACBD5 knockdown led to decreased synapse formation and neuronal activity. 11/13

Knockdown of VAPB and ACBD5, tethering proteins that mediate ER-peroxisome contacts, reduced ether lipid and plasmalogen synthesis in iNeurons at day 14. 10/13

What do ER-peroxisomes contacts do? These are a key hub for ether lipid and plasmalogen biosynthesis. Plasmalogens stabilize curved membrane surfaces and are highly enriched at #synapses and in synaptic vesicles. 9/13

We found that ER-mitochondria and mitochondria-peroxisome contacts significantly correlated with the expression of tether proteins MNF2 and ACBD5 at day 7. As iNeurons mature at day 14, we discovered that ER-peroxisome contacts significantly correlated with ACBD5. 8/13

A great thing about the KOLF2.1J stem cell line is that it is very well characterized, because it is the parental line for the iNDI library. Thus, we could correlate our microscopy with a complementary proteomics data set generously provided by Andy Qi (doi.org/10.1101/2025...). 7/13

The network rewires in phases: mitochondria emerge as an early hub, consistent with metabolic remodeling as cells shift from glycolysis to oxidative phosphorylation. Later, ER-organelle contacts dominate, pointing to a shift toward lipid remodeling and membrane specialization. 6/13

Organelle communication increase as stem cells differentiate into neurons, as observed by an increase in 2-, 3-, and 4-way contacts number and volumes. These organelle interactions facilitate exchange of ions, lipids, and information. 5/13

Differentiation drives major changes in cell and organelle geometry: soma shrinks while neurites increase, and most organelles rescale with their compartment volume. 4/13