Frances M. Platt
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View article: Miglustat as a Treatment for Adults with Tangier Disease Neuropathy: The MUSTANG N-of-1 Trial with 21 months Clinical Observation
Miglustat as a Treatment for Adults with Tangier Disease Neuropathy: The MUSTANG N-of-1 Trial with 21 months Clinical Observation Open
ClinicalTrials.gov Identifier: ISRCTN17945917. Registration date: 07/06/2021; 'retrospectively registered'.
Profiling glycosphingolipid changes in mouse and human cellular models of lysosomal free sialic acid storage disorder Open
Free sialic acid storage disorder (FSASD) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic variants in SLC17A5, which encodes the lysosomal sialic acid transporter, sialin. FSASD is characterized by excess…
Glycoprotein non-metastatic melanoma protein B is a biomarker of inflammation in individuals with Gaucher disease: relationship to clinico-pathological subtypes Open
Background Gaucher disease (GD) is a lysosomal disease caused by mutations in the GBA1 gene, leading to glucosylceramide and glucosylsphingosine accumulation. GBA1 mutations are also the most common genetic risk factor for Parkinson’s dise…
View article: Alternate Splicing Directs PMCA2 to Lysosomes and is Linked to Neurodegeneration
Alternate Splicing Directs PMCA2 to Lysosomes and is Linked to Neurodegeneration Open
Plasma membrane calcium ATPase (PMCAs) are believed to function exclusively at the plasma membrane where they expel calcium from the cytosol. We have unexpectedly identified a splice variant-dependent localisation of the PMCA isoform PMCA2…
A pathogenic alpha synuclein variant exacerbates disease progression in a neuron-specific Gba-KO mouse Open
GBA variants are among the most significant genetic risk factors for synucleinopathies including Parkinson's disease and dementia with Lewy bodies. The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GBA), which is essential for …
View article: Mono-allelic p.R37H Dehydrodolichyl Diphosphate Synthase variants lead to protein glycosylation defects, aberrant lipid profiles and interneuron scarcity in a novel mouse model of progressive epileptic encephalopathy
Mono-allelic p.R37H Dehydrodolichyl Diphosphate Synthase variants lead to protein glycosylation defects, aberrant lipid profiles and interneuron scarcity in a novel mouse model of progressive epileptic encephalopathy Open
Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectru…
Plasma membrane remodeling in GM2 gangliosidoses drives synaptic dysfunction Open
Glycosphingolipids (GSL) are important bioactive membrane components. GSLs containing sialic acids, known as gangliosides, are highly abundant in the brain and diseases of ganglioside metabolism cause severe early-onset neurodegeneration. …
Dissecting the impact of N-acetylmannosamine (ManNAc) on ganglioside levels in a sialin-deficient cell model Open
Lysosomal free sialic acid storage disorder (FSASD) is an ultra-rare neurodegenerative condition caused by mutations in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. Deficiency of sialin leads to lysosomal accumulation…
Analysis of sphingosine, sphinganine and glucosylsphingosine from cells, animal tissues and plasma v1 Open
Sphingosine (SphO), sphinganine (SphA) and glucosylsphingosine (GlcSph) are crucial molecules involved in sphingolipid metabolism.Sphingosine and sphinganine are long-chain bases that serve as building blocks for more complex sphingolipids…
Investigating the Utility of Leukocyte Sialic Acid Measurements in Lysosomal Free Sialic Acid Storage Disorder Open
Lysosomal free sialic acid storage disorder (FSASD) is a rare, multisystem neurodegenerative disease caused by biallelic pathogenic variants in SLC17A5 , encoding sialin. FSASD is characterized by aberrant accumulation of unconjugated “fre…
Stereospecific rapid activation of Transcription Factor EB (TFEB) by Levacetylleucine (NALL) Open
N-acetyl L-leucine (NALL, USAN or levacetylleucine, INN or trade name Aqneursa™) is an FDA-approved agent for the treatment of Niemann-Pick disease type C (NPC). The N-acetyl group renders the compound a prodrug of L-leucine, making it a s…
Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies Open
Autosomal recessive cerebellar ataxias (ARCAs) represent over 200 clinically heterogeneous genetic conditions involving degeneration of the cerebellum and associated tracts with resultant impairment of balance and coordination. Advancement…
N-Acetyl-l-Leucine (NALL) rescues inter-organelle communication in Niemann-Pick disease type-C patient cells Open
Niemann-Pick disease type-C (NPC) is a progressive neurodegenerative disease caused by loss-of-function mutations in NPC1 or NPC2 . In NPC patient cells lacking functional NPC proteins, lipids accumulate in lysosomes causing severe lysosom…
Pharmacological profiling of small molecule modulators of the TMEM16A channel and their implications for the control of artery and capillary function Open
Background and purpose TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action …
View article: Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease
Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease Open
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysoso…
Deletion of Gba in neurons, but not microglia, causes neurodegeneration in a Gaucher mouse model Open
Gaucher disease, the most prevalent lysosomal storage disease, is caused by homozygous mutations at the GBA gene, which is responsible for encoding the enzyme glucocerebrosidase. Neuronopathic Gaucher disease is associated with microgliosi…
Plasma Membrane Remodelling in GM2 Gangliosidoses Drives Synaptic Dysfunction Open
Glycosphingolipids (GSL) are important bioactive components of cellular membranes. Complex GSLs, containing sialic acid residues are known as gangliosides and are highly abundant in the brain. Diseases of ganglioside metabolism often resul…
View article: The annotation of <i>GBA1</i> has been concealed by its protein-coding pseudogene <i>GBAP1</i>
The annotation of <i>GBA1</i> has been concealed by its protein-coding pseudogene <i>GBAP1</i> Open
Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson’s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1 . We show that >50% …
Lysosomal signalling pathways influence heart rhythm, and regulate atrial function Open
In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium release to augment sarcoplasmic reticulum (SR) calcium sequestration, producing larger calcium transients. However, the role of lysos…
View article: Lysosomal signalling pathways influence heart rhythm, and regulate atrial function
Lysosomal signalling pathways influence heart rhythm, and regulate atrial function Open
In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca 2+ ) release to augment sarcoplasmic reticulum [1] Ca 2+ sequestration, producing larger Ca 2+ transients. However, the role of l…
Plasma phosphorylated-tau217 is increased in Niemann–Pick disease type C Open
Niemann–Pick disease type C and Alzheimer’s disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology. In this multicentre study, we measured plasma phosphorylated-tau217 in controls (n = …
The expanding boundaries of sphingolipid lysosomal storage diseases; insights from Niemann–Pick disease type C Open
Lysosomal storage diseases are inborn errors of metabolism that arise due to loss of function mutations in genes encoding lysosomal enzymes, protein co-factors or lysosomal membrane proteins. As a consequence of the genetic defect, lysosom…
View article: Cholera intoxication of human enteroids reveals interplay between decoy and functional glycoconjugate ligands
Cholera intoxication of human enteroids reveals interplay between decoy and functional glycoconjugate ligands Open
Prior research on cholera toxin (CT) binding and intoxication has relied on human colonic cancer derived epithelial cells. While these transformed cell lines have been beneficial, they neither derive from small intestine where intoxication…