Amazing work by Ryohei Watanabe!.

Maybe my last Tweet?.We found that shifting around polyubiquitin (using a chemical biology trick) results in altered #tau filament structure. The unstructured "fuzzy coat" of tau filaments matters!?! #AD #FTD #FTLD #cryoEM #Alzheimer #VCP #raredisease .

What do you want to know?.

I've started writing a new grant in anticipation of the RFAs that are coming in 2025. "Synergistic effects of fluorinated water and lecanemab on autism risk in Alzheimer's Disease." 🤮🤯😖☠️.

For my daughter, wife, mother, I #vote.

RT @PennMedCSO: .@PennMedicine researchers receive $18M grant from @NIH/@NIHAging to investigate cognitive decline in Lewy body diseases ft….

RT @DrNeuroChic: You ever meet someone who you know will help change the world just by existing. then you get to know them and see how muc….

Thrilling to give the #AAIC24 introductory plenary about how neuropathology synergizes with other disciplines. Nerve-wracking and exhilirating! Thank u @alzassociation scientific planning committee for giving me the honor of welcoming everyone to Philly. #inclusion #diversity

Welcome to Philly!

RT @bwfalcon: Well this was unexpected! We found that TDP-43 forms heteromeric amyloid filaments with a second protein, annexin A11, in the….

Interesting that p.G38R and p.P75S, which are associated with annexinopathy, both flank the annexin A11 core sequence.

Amazing and beautiful cryoEM structure of heteromeric TDP-43 and annexin A11 filaments from FTLD-TDP Type C. I didn't know they found this when we published our paper on annexinopathy in FTLD-TDP Type C - the timing is crazy!.

Awesome collaboration with @vivivandeerlin_ @silvia_porta0, EunRan Suh, John Robinson (JR), and our clinical colleagues in the @PennFTDCenter, Penn PD and Movement Disorders Center, and Penn Comprehensive ALS Center.

Annexinopathies (sporadic and genetic) are associated with accumulation of biochemically insoluble, full length and truncated annexin A11 protein.

We also discovered a novel p.P75S ANXA11 variant associated with a PSP-like clinical syndrome & ubiquitinated, neuritic annexin A11 aggregates (no TDP-43/tau/alpha-synuclein/FUS). We are calling this new entity "vacuolar annexinopathy" due to prominent striatial vacuolization.

Here's annexin A11 (green) and TDP-43 (red) colocalizing in a motor neuron skein-like inclusion in a case of #ALS due to a pathogenic p.G38R ANXA11 variant.

We also found annexin A11 co-accumulating with TDP-43 in ~5% other types of FTLD-TDP, LATE and #ALS.

Surprise - FTLD-TDP Type C is a dual proteinopathy! Annexin A11 co-accumulates with TDP-43 in all cases of FTLD-TDP Type C. #annexinopathy.#FTD #dementia #ADRD #ActaNeuropathologica.

Congratulations to Jessica Phan and Ben Creekmore (@FutureDrDrB) for this excellent study!.

We hope to further optimize small molecule VCP activators with an eye towards treating diseases with ubiquitinated protein aggregates: Alzheimer's disease, frontotemporal dementia, inclusion body myopathy, Paget's disease of bone and others.

We hypothesized that these "overactive" VCP mutations result in a loss of nuclear function due to mislocalization. Consistent with this, VCP inhibitors exacerbate nuclear protein (TDP-43) aggregation while our novel VCP activators help clear nuclear protein aggregates.