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Background Loss-of-function mutations in the progranulin (PGRN) gene (GRN) are a major cause of Frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD). PGRN is a lysosom...

Flortaucipir uptake in FTLD-TDP, particularly type C, could reflect off-target binding to phosphorylated TDP-43 and ANXA11 aggregates in limbic regions rather than tau pathology alone; consequently, t...

Company behind .bank and .insurance is looking for a new leader. A longtime fixture in the domain name business is retiring, opening up an interesting job opportunity. Craig Schwartz, president of fTLD, announced that he is retiring in Q2 2027. He's led the company since 2011, after spending five years at ICANN. fTLD manages the highly controlled .bank and .insurance top level domain names.

Background This study characterised overall transdiagnostic associations between psychological and behavioural symptoms and carer burden, and examined syndrome-specific contributions across clinically...

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Last note. If this S-GEVs → c9orf72 als gene therapy shows to be valid, it **absolutely** should apply to #FTLD since the defect is the same defect!

Eight microscope images compare brain tissue from FTLD-TDP type A and LATE-NC. The first four panels show tissue from the middle frontal gyrus stained with H&E and TDP-43, highlighting abnormal TDP-43 protein deposits inside nerve cells and their processes. The remaining panels show a FTLD-TDP type A case with a greater burden of TDP-43 pathology in other brain regions, including the subgenual cingulate, entorhinal cortex and superior temporal gyrus. The figure illustrates that examining only the middle frontal gyrus may not reliably distinguish FTLD-TDP type A from LATE-NC.

Dominant mutations in progranulin (GRN) gene cause frontotemporal lobar degeneration (FTLD-GRN), whereas homozygous GRN mutations lead to neuronal ceroid lipofuscinosis, a childhood neurodegenerative disorder. While recent transcriptomic studies reveal profound glial and neuronal pathology in FTLD-GRN at the disease end stage, the mechanism that disrupts glia-neuron homeostasis remains unclear. Using induced pluripotent stem cell–derived cortical organoids, we showed that GRN–/– and GRNR493X mutations led to precocious astrogliosis that promoted neuronal stress and synaptic loss. Single-cell transcriptomics and histopathology analyses revealed a robust activation in the TGF-β signaling pathway in GRN–/– and GRNR493X/R493X astrocytes, which was accompanied by features of immune activation, loss of synaptic support, and abundant pTDP-43+ fibrils in astroglial cytoplasm, a feature characteristic of FTLD-GRN. Intriguingly, blocking TGF-β signaling mitigated astroglial activation and pTDP-43 proteinopathy in GRN–/– organoids. Together, these results provide insights into the cell-autonomous role of astroglial activation in neurodegeneration caused by progranulin deficiency.

Read the full paper: FTLD‐TDP versus LATE‐NC: Experience of a Brain Bank specializing in FTLD‐TDP

The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philan...

Phase separation (PS) of the low-complexity domain (LCD) of TDP-43 is linked to pathogenic aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). Here, we show that extensive phosphorylation of the LCD C-terminus redirects its self-assembly. Coarse-grained Monte Carlo simulations predicted that 12 Ser phosphorylations partition the 148-residue LCD into a hydrophobic N-terminal and highly charged C-terminal block, favoring finite-sized micellization over macroscopic PS. In vitro, LCD phosphorylated by casein kinase 1 delta (CK1{delta}; mean of 12 phosphorylations by native mass spectrometry) and phosphomimetic 12D/12DD mutants formed spherical nanoparticles ({approx} 20-50 nm) above a low-micromolar critical micelle concentration, whereas the unphosphorylated LCD underwent reversible PS that matured into fibrils. Increasing ionic strength shifted the mutants toward anisotropic morphologies (worm-like 12D micelles and rigid 12DD nanocylinders). Turbidity assays and confocal imaging directly visualized the absence of PS in the phosphorylated form. Negative-stain and cryo-EM confirmed the spherical micellar architecture for the phosphorylated LCD and 12D/12DD mimics. Our data identify phosphorylation as a molecular switch tuning macrophase separation and fibril formation of TDP-43 LCD, providing a framework for an aggregation-protective role through microphase separation into size-limited micelles. Whether these assemblies are stable or kinetically trapped on pathological timescales remains unclear.

.bank is a generic top level domain (gTLD) used in the Domain Name System of the internet. The TLD