Biology subjects

Dobson-Stone, C.

Publications and source records attributed to Dobson-Stone, C..

4 recordsLinked to original sources

bioRxiv2025

Reduced plasma hexosylceramides in frontotemporal dementia are a biomarker of white matter integrity

INTRODUCTIONBlood biomarkers are needed to facilitate new therapeutic trials and improve management of behavioural variant frontotemporal dementia (bvFTD). Since altered white matter integrity is characteristic of bvFTD, this study aimed to determine if plasma levels of myelin-enriched glycolipids are altered in bvFTD and correlate with white matter integrity. METHODSNineteen glycolipids were quantified in bvFTD (n=31) and control (n=26) plasma samples. White matter integrity was assessed using MRI-derived fibre tract density and cross-section (FDC). RESULTSEleven lipids were significantly lower in bvFTD compared to control subjects, seven were inversely correlated with disease duration, and twelve were positively correlated with cognitive performance, with C22:0 hexosylceramide most strongly correlated. FDC was lower in frontotemporal white matter tracts of bvFTD compared to control subjects, and plasma C22:0 hexosylceramide was significantly correlated with FDC in these tracts. DISCUSSIONCirculating glycolipids may be a valuable biomarker of myelin integrity and disease progression in FTD.

neuroscience↗

bioRxiv2022

TDP-43 subcellular mislocalisation is correlated with loss of optineurin binding for frontotemporal dementia and amyotrophic lateral sclerosis associated TBK1 missense variants

BackgroundFrontotemporal dementia (FTD) is one of the most common forms of younger-onset dementia. FTD is genetically, pathologically and clinically related to amyotrophic lateral sclerosis (ALS), a rapidly progressive neurodegenerative disorder. Mutations in TANK-binding kinase 1 (TBK1) have been identified as a rare cause of FTD and ALS. TBK1 has known roles in inflammation and autophagy and interacts with other FTD and ALS proteins such as optineurin (OPTN): however, which of its roles are important to FTD/ALS pathogenesis remains undetermined. To date, >90 TBK1 rare variants have been identified in FTD/ALS patients: >50% of these are missense variants of unknown significance (VUS). MethodsIn this study, we have used a functional assay pipeline to investigate the effect of 16 TBK1 VUS with in-silico evidence of pathogenicity, together with two known pathogenic mutations and a common benign TBK1 polymorphism. Our assay pipeline evaluated the effect of TBK1 VUS on steady-state levels of TBK1, kinase activity and binding to OPTN. We also assessed the impact of TBK1 VUS on a key neuropathological feature of FTD and ALS cases: mislocalisation of neuronal TDP-43 from the nucleus to the cytoplasm. ResultsWe observed some TBK1 VUS that had similar effects to TBK1 loss-of-function mutations, demonstrating decreased kinase activity and loss of OPTN binding. Both known pathogenic mutations and several TBK1 VUS also increased the cytoplasmic/nuclear ratio of TDP-43 and this inversely correlated with their degree of OPTN binding but not with kinase activity. ConclusionsThese results suggest that loss of the direct interaction between TBK1 and OPTN is more critical to FTD and ALS pathogenesis than TBK1s kinase activity. However, further studies are needed to elucidate exactly how loss of TBK1 binding to OPTN leads to TDP-43 pathology and ultimately neurodegeneration.

genetics↗

bioRxiv2021

Rapid and automated quantification of TDP-43 and FUS mislocalisation for screening of frontotemporal dementia and amyotrophic lateral sclerosis gene variants

BackgroundIdentified genetic mutations cause 20% of frontotemporal dementia (FTD) and 5-10% of amyotrophic lateral sclerosis (ALS) cases: however, for the remainder of patients the origin of the disease is uncertain. The overlap in genetic, clinical and pathological presentation of FTD and ALS suggests these two diseases are related. Post-mortem, 97% of ALS and [~]50% of FTD patients show redistribution of the nuclear proteins TDP-43 or FUS to the cytoplasm within affected neurons. We exploited this predominant neuropathological feature to develop an automated method for the quantification of cytoplasmic TDP-43 and FUS in human cell lines. ResultsUtilising fluorescently-tagged cDNA constructs to identify cells of interest, the fluorescence intensity of TDP-43 or FUS was measured in the nucleus and cytoplasm of HEK293 and SH-SY5Y cells. Confocal microscope images were input into the freely available software CellProfiler, which was used to isolate and measure the two cellular compartments. Significant increases in the amount of cytoplasmic TDP-43 and FUS were detectable in cells expressing known ALS-causative TARDBP and FUS gene mutations. Pharmacological intervention with the apoptosis inducer staurosporine also induced measurable cytoplasmic mislocalisation of endogenous FUS. Additionally, this technique was able to detect the subtler effect of mutation in a secondary gene (CYLD) on endogenous TDP-43 localisation. ConclusionsThese findings validate this methodology as a novel in vitro technique for the quantification of TDP-43 or FUS mislocalisation that can be used to assess the pathogenicity of predicted FTD- or ALS-causative mutations.

molecular biology↗

bioRxiv2019

Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

genetics↗