2026-08-13 | The Interactions of Tau, RNA, and Stress Granules in Neurodegenerative Disease: A Comprehensive Review.

The discovery of RNA in the late 19th century revolutionized the understanding of cell biology. Subsequent discoveries over the next six decades revealed a key role for RNA in protein synthesis. Nevertheless, today, the mechanisms driving RNA metabolism remain enigmatic. Given its fundamental cellular role, RNA alterations are strongly linked to disease, including devastating neurodegenerative disorders pathologically defined by the accumulation of RNA-binding proteins. For example, the mislocalization of TDP-43, an RNA-binding protein, is a pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia TDP-43. Another group of more than 20 neurodegenerative disorders, called tauopathies, is characterized by the aberrant accumulation of the protein tau. Similarly, the emerging concept that tau binds RNA, facilitating the formation of pathological structures, highlights the importance of RNA stability in tauopathies. However, the dynamics and consequences of RNA-tau interactions remain unclear. This review comprehensively catalogs key findings linking tau, RNA, and stress granules. These findings are important because they could offer novel opportunities to design therapeutic strategies.

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2026-08-13 | Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.

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2026-08-05 | Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.

The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.

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2026-08-04 | Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors.

Lysosomal dysfunction in myeloid cells is increasingly implicated in neurodegenerative diseases. To examine the interplay between lysosomal health and cellular state, we performed multi-omic profiling of myeloid cells from brains of aged mice lacking progranulin (Grn-/- mice), a lysosomal protein linked to neurodegeneration. Single-cell RNA sequencing identified a microglial subpopulation defined by GPNMB expression, which displays hallmarks of lysosomal stress, including altered lysosomal protein expression, lipofuscinosis, and metabolic and lipid dysregulation. Epigenetic profiling of Grn-/- microglia revealed an enrichment of MITF/TFE transcription factor motifs at active enhancers, and deletion of these factors reversed the Grn-/--specific myeloid cell transcriptional signature. Diverse lysosomal perturbations drove a common transcriptional and functional signature, with conditions that induce lysosomal deacidification closely phenocopying progranulin deficiency. Finally, compensatory GPNMB induction in Grn-/- myeloid cells promoted lysosomal acidification, and loss of myeloid cell GPNMB exacerbated neurotoxicity. Our findings link lysosomal health with epigenetic, transcriptional, and functional myeloid cell states associated with neurodegeneration.

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2026-08-04 | Neuron-specific suppression of aberrantly active Toll-NFκB signalling mitigates pathogenic tau hyperphosphorylation via Gsk-3β in Drosophila.

Chronic brain ailments like Alzheimer's disease and Frontotemporal dementia, together referred to as tauopathies, are strongly influenced by neuroinflammation, an age-associated functional anomaly. Neuroinflammation arising from a dysfunctional innate immune response, such as Toll-NFκB signalling, is implicated in modulating tau pathophysiology, with limited understanding of the molecular mechanisms. Pathogenic hyperphosphorylation of tau and its aggregation into neurotoxic species is considered as a central trigger of tau pathology; however, the mechanistic association between these pathogenic events and the Toll signalling remains largely unexplored. We examined the status of the Toll signalling in Drosophila tauopathy models and evaluated whether its modulation modifies disease severity. We present compelling evidence that neuronal expression of pathogenic human tau causes aberrant activation of the Toll signalling. In line, its additional upregulation further aggravates disease severity, while genetic downregulation of Toll components remarkably alleviates both structural and functional deficits. We subsequently noted that knockdown of the Toll pathway attenuates pathogenic tau hyperphosphorylation in a site-specific manner, largely coinciding with restoration of physiological activity of Gsk-3β/Akt/PP2Ac signalling, a relatively less explored molecular axis in neurons. Our study posits a potential contribution of neuron-intrinsic altered Toll signalling cascade in tau pathogenesis, warranting further exploration of this evolutionarily conserved pathway as a therapeutic target.

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