🧵New paper from the lab @isd-research.bsky.social @lmu-klinikum.bsky.social @lmu.de in STM @science.org! A human #iPSC-derived #Tauopathy model that endogenously develops late-stage Tau pathology. Free personal PDF: www.science.org/eprint/5H5YD....
Here's what we found👇 1/10

📝 Now online - the Review "Molecular and structural mechanisms of nutrient sensing in the mTORC1 pathway" from @robzonculab.bsky.social and co.

#mTORC1 #PrimaryNutrientSensor #AminoAcidSensor #CholesterolSensor #Metabolites

Read it here: authors.elsevier.com/a/1mrsu_M0e4...

Sharing again for weekday feeds.

Also see beautiful parallel study from Aaron Gitler and Monther Abu-Remaileh, where they independently show that GRN and TMEM106B variants regulate levels of the fibril core domain. www.biorxiv.org/content/10.6...

This work was led by three outstanding trainees: John Replogle, Jordan Marks, and Martin Fernandez. Their creativity and hard work made this possible, along with efforts from many others across multiple labs.

In post-mortem FTLD-GRN brain, we find these intra-lysosomal fibrils associated with ruptured lysosomes. Reducing their formation or clearing them may represent a new therapeutic target for dementia.

TMEM106B is also a lysosomal protein. Its cleaved intra-luminal fibril core domain forms within the lysosome and serves as the direct precursor to these fibrils, which accumulate inside the very compartment responsible for their clearance.

Disease-associated variants in these genes drive neurotoxic TMEM106B amyloid fibril accumulation. A coding TMEM106B variant impairs fibril degradation, while GRN variants amplify accumulation through reduced intra-lysosomal progranulin, a lysosomal protein.

For 16 years, TMEM106B and GRN variants have ranked among the strongest genetic risk factors for dementia. We finally have a mechanistic answer for why. www.biorxiv.org/content/10.6...

CryoET and colored segmentation of TMEM106B fibrils protruding from within a broken lysosome in post-mortem FTLD-GRN brain.

Excited to share a pre-print from a collaboration between my lab at NIH, Len Petrucelli's lab at University of Miami, and Shyamal Mosalaganti's lab at University of Michigan.

In post-mortem FTLD-GRN brain, we find these intra-lysosomal fibrils associated with ruptured lysosomes. Reducing their formation or clearing them may represent a new therapeutic target for dementia.

TMEM106B is also a lysosomal protein. Its cleaved fibril core domain accumulates within the lysosome and serves as the direct precursor to these fibrils, forming inside the very compartment responsible for their clearance.

Disease-associated variants drive neurotoxic TMEM106B fibril accumulation inside lysosomes. A coding TMEM106B variant impairs fibril degradation, while GRN variants amplify accumulation through reduced intra-lysosomal progranulin, also a lysosomal protein.

For 16 years, TMEM106B and GRN variants have ranked among the strongest genetic risk factors for dementia. We finally have a mechanistic answer for why. www.biorxiv.org/content/10.6...

n post-mortem FTLD-GRN brain, we find these intra-lysosomal fibrils associated with ruptured lysosomes. Reducing their formation or clearing them may represent a new therapeutic target for dementia.

TMEM106B is also a lysosomal protein. Its cleaved fibril core domain accumulates within the lysosome and serves as the direct precursor to these fibrils, forming inside the very compartment responsible for their clearance.

Disease-associated variants in these genes drive neurotoxic TMEM106B fibril accumulation inside lysosomes. A coding TMEM106B variant impairs fibril degradation, while GRN variants amplify accumulation through reduced intra-lysosomal progranulin, also a lysosomal protein.

For 16 years, TMEM106B and GRN variants have ranked among the strongest genetic risk factors for dementia. We finally have a mechanistic answer for why.

Excited to share a pre-print from a collaboration between my lab at NIH, Len Petrucelli's lab at University of Miami, and Shyamal Mosalaganti's lab at University of Michigan. www.biorxiv.org/content/10.6...

Check out the newest work from our, from Fabricio Nicola @fabricionicola.bsky.social on mouse jumping and spinal cell types.

Excellent collab with @vulcnethologist.bsky.social

www.biorxiv.org/content/10.6...

How Congress can restore the independence of US science Members must go beyond reinstating US government research spending and re-establish decentralized governance at the National Institutes of Health and other agencies.

The most impt change at #NIH and to US science this year is bigger than grant cancellations— it’s how the agency is governed.

For 75 years NIH has been largely independent of presidential control. That’s changed this year. New piece from me and @nataliebaviles.bsky.social in @nature.com
🧪

Temporal proteomic and phosphoproteomic dynamics during neuronal differentiation in the reference iPSC line KOLF2.1J Trace protein and phosphoprotein dynamics during neuronal differentiation in the iPSC-derived cell line model are described.

A new #ScienceSignaling study offers insights into the KOLF2.IJ cell line, which is derived from induced pluripotent stem cells and has been proposed as a neuronal model for Alzheimer’s disease and related #dementia research. https://scim.ag/4aFNY9O

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...

Losing sleep over #iPSC transgene silencing after differentiation?
Same here.

Bright in iPSCs.
Gone after differentiation.

Our paper in @cp-cellstemcell.bsky.social maps what actually keeps expression on👇
www.cell.com/cell-stem-ce...
🔗 Free access (50 days):
www.sciencedirect.com/science/auth...

Thrilled to see our paper out in @cp-cellstemcell.bsky.social!

www.biorxiv.org/content/10.6...

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis CRISPR screens in iPSC-derived neurons reveal that the E3 ubiquitin ligase CRL5SOCS4 ubiquitinates tau, that CUL5 expression is correlated with resilience in human Alzheimer’s disease, and that electr...

www.cell.com/cell/fulltex...

We have had great luck with these kits (and the dyes are quite bright): biotium.com/product/mix-...

But honestly prefer secondary nanobody pre-mixing with primaries (site specific and slow off kinetics): nano-tag.com/technology/s...

TDP-43 dysfunction leads to the accumulation of cryptic transposable element-derived exons, crypTEs, in iPSC derived neurons and ALS/FTD patient tissues TDP-43 is an RNA and DNA binding protein that plays major roles in regulating RNA processing. In particular, TDP-43 dysfunction leads to the accumulation of cryptic splice isoforms that result from im...

📣Excited to announce a new pre-print from the lab 📣

Led by my student @storiesofisobel.bsky.social in collab with Hemali Phatnani @nygenome.org
We discovered a novel class of TDP-43 dependent cryptic gene-TE spliced transcripts: crypTEs

#TEsky #RNAsky #ALS
doi.org/10.64898/2026.01.09.698641

Latest preprint from our lab reports that the distinct pH of anterograde (less acidic) and retrograde (more acidic) lysosomal vesicles in the axon depends on assembly of the V1 and V0 domains of the vacuolar H+ ATPase, mediated by the metazoan RAVE complex www.biorxiv.org/content/10.6...