Biology subjects

Ghayal, N. B.

Publications and source records attributed to Ghayal, N. B..

3 recordsLinked to original sources

bioRxiv2026

Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants

Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP. Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergoprogressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

genetics↗

bioRxiv2025

TAF15 amyloids propagate via defined motifs in a prion-like fashion

TATA-box binding protein-associated factor 15 (TAF15) is an RNA-binding member of the FET family recently identified as the primary fibrillar constituent in a subset of frontotemporal lobar degeneration (FTLD-FET) cases. Although TAF15 is also linked to amyotrophic lateral sclerosis (ALS), the molecular basis and propagation behavior of its aggregates remain unknown. In this work, we show that recombinant TAF15 forms amyloid fibrils under physiological conditions and developed a single-fluorophore TAF15 biosensor to quantitatively monitor their cellular propagation. Using this system, we demonstrate that both recombinant TAF15 fibrils and pathological aggregates extracted from atypical FTLD with ubiquitin inclusions (aFTLD-U) patient brains seed aggregation efficiently and transmit serially between cells, demonstrating hallmark features of prion-like propagation. Seeding was specific to TAF15 and absent for other amyloidogenic proteins, including the homologous protein fused-in-sarcoma (FUS), revealing an unexpected cross-seeding barrier. Occasional colocalization of FUS within TAF15 inclusions was observed upon transient co-expression, suggesting that FUS can be passively recruited rather than acting as an inducer of pathology in FTLD-FET brains. Computational and peptide-based experimental mapping identified multiple aggregation-prone regions within the TAF15 low-complexity domain that coincide with hotspots stabilizing the core of ex vivo TAF15 amyloid fibrils. These short motifs encode the propagation propensity of TAF15 aggregation in vitro and in cells. Together, these findings establish TAF15 as a bona fide amyloid-forming, prion-like protein and define the sequence grammar underlying its self-assembly, providing a mechanistic framework for its role in FTLD-FET and ALS and offering tractable molecular targets for therapeutic intervention.

biophysics↗

bioRxiv2025

Expanding the spectrum of annexin A11 proteinopathy in frontotemporal lobar degeneration and motor neuron disease

Aggregation of TAR DNA-binding protein 43 (TDP-43) is strongly associated with frontotemporal lobar degeneration (FTLD-TDP), motor neuron disease (MND-TDP), and overlap disorders like FTLD-MND. Three major forms of motor neuron disease are recognized and include primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and progressive muscular atrophy (PMA). Annexin A11 (ANXA11) is understood to aggregate in amyotrophic lateral sclerosis (ALS-TDP) associated with pathogenic variants in ANXA11, as well as in FTLD-TDP type C. Given these observations and recent reports of ANXA11 variants in patients with semantic variant frontotemporal dementia (svFTD) and FTD-MND presentations, we sought to characterize ANXA11 proteinopathy in an autopsy cohort of 379 cases with FTLD-TDP, as well as FTLD-MND and MND-TDP cases subclassified neuropathologically into PLS, ALS, and PMA. All FTLD-TDP type C cases had ANXA11 proteinopathy. However, ANXA11 proteinopathy was present in over 40% of FTLD-MND and in 38 out of 40 FTLD-PLS cases (95%), of which 80% had TDP type B or an unclassifiable TDP-43 proteinopathy and 15% had TDP type C. Genetic analyses excluded pathogenic ANXA11 variants in all ANXA11-positive cases. We thus demonstrated novel forms of ANXA11 proteinopathy strongly associated with FTLD-PLS, but not with TDP type C or pathogenic ANXA11 variants. Given the emerging relationship of ANXA11 in TDP-43 proteinopathies, we propose that TDP-43 and ANXA11 proteinopathy (TAP) comprises the molecular pathology of cases with abundant inclusions that are co-immunoreactive for both proteins and we subclassify three types of TAP based on distinct clinical and neuropathologic features.

neuroscience↗