A5059141377- Parkinson's Disease Mechanisms and Treatments
- Lymphoma Diagnosis and Treatment
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Mycobacterium research and diagnosis
- Metabolism and Genetic Disorders
- Ion channel regulation and function
- Epigenetics and DNA Methylation
- Nuclear Receptors and Signaling
- Chronic Lymphocytic Leukemia Research
- Neuroscience and Neuropharmacology Research
- Botulinum Toxin and Related Neurological Disorders
- RNA regulation and disease
- Lysosomal Storage Disorders Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Chronic Myeloid Leukemia Treatments
- Image Processing and 3D Reconstruction
- CRISPR and Genetic Engineering
- Neurological disorders and treatments
- PI3K/AKT/mTOR signaling in cancer
- Cannabis and Cannabinoid Research
- Nicotinic Acetylcholine Receptors Study
- ATP Synthase and ATPases Research
- Solid-state spectroscopy and crystallography
- Neurological diseases and metabolism
University College London
2018-2025
National Hospital for Neurology and Neurosurgery
2018-2025
Research Network (United States)
2022-2024
University of London
2024
Universidad Complutense de Madrid
2023
Aligning Science Across Parkinson's
2023
King's College London
2022
Alzheimer’s Research UK
2022
UK Dementia Research Institute
2022
Neuroscience Institute
2022
Abstract AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients intellectual disability (ID) neurodevelopmental...
Abstract Parkinson’s disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding the risk. Understanding functional significance risk loci now critical step towards translating these advances into an enhanced biological Impaired mitophagy key causative pathway in familial disease, but its relevance to idiopathic unclear. We used screening assay evaluate genes identified through...
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% individuals affected PFBC no molecular diagnosis. We report four unrelated families presenting initial learning difficulties seizures later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs,...
Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be neural circuit with dysfunction arising within between multiple brain regions. Given that spinal circuits constitute the final pathway for motor control, we sought determine their contribution this movement disorder. Focusing on most common inherited form of dystonia in humans, DYT1- TOR1A , generated conditional knockout torsin family 1 member A ( Tor1a ) gene mouse cord dorsal...
Parkinson's disease is a progressive neurological disorder, characterized by prominent movement dysfunction. The past two decades have seen rapid expansion of our understanding the genetic basis Parkinson's, initially through identification monogenic forms and, more recently, genome-wide association studies identifying common risk variants. Intriguingly, number cellular pathways emerged from these analysis as playing central roles in aetiopathogenesis Parkinson's. In this review, impact data...
Protocol outlining the use of immunoblots for assessment PINK1-dependent mitophagy process in iNeurons.
Protocol for the imaging and analysis of iNeurons with anti-pUb(Ser65) immunofluorescence in order to measure PINK1-dependent mitophagy initiation.
Protocol for the extraction of RNA from iNeurons and RT-qPCR measurements PINK1 mRNA.
An inversion polymorphism at the 17q21.31 locus defines H1 and H2 haplotypes, with former linked to multiple neurodegenerative disorders, including an increased risk of Parkinson's disease (PD). Although high linkage disequilibrium this has made it difficult decipher which gene(s) drive PD association, there is increasing evidence support role KANSL1 as a gene. been shown regulate expression some PD-associated genes pathways, likely part histone acetylating non-specific lethal (NSL) complex....
The genetics of Parkinson’s disease has been key to unravelling the PINK1-dependent mitophagy process. Here, we discuss implications a 2010 PLOS Biology paper that shed light on functional importance PINK1 in cascade.
Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle associated with low serum potassium. Muscle fibre inexcitability during attacks due to an aberrant depolarizing leak current through mutant voltage sensing domains either the sarcolemmal voltage-gated calcium or sodium channel. We report child hypokalaemic and CNS involvement, including seizures, but without mutations in known genes. identified novel heterozygous de novo...
Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes identification potential biomarkers therapeutic targets. Here, we identify
Abstract It has recently been shown that KAT8 , a genome-wide association study candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependant mitophagy. The encodes lysine acetyltransferase and represents the catalytically active subunit of non-specific lethal epigenetic remodelling complex. In current study, we show contrary to KAT5 inhibition, dual inhibition via MG149 compound inhibits initial steps PINK1-dependant mitophagy process. More specifically, our shows...
ABSTRACT Parkinson’s disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding the PD risk. Understanding functional significance risk loci now critical step towards translating these advances into an enhanced biological Impaired mitophagy key causative pathway in familial PD, but its relevance to idiopathic unclear. We used screening assay evaluate genes...
To understand the role of angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IAs), we investigated its a large cohort familial IAs.Individuals with family history IA were recruited to Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 was sequenced using Sanger sequencing. Identified genetic variants compared control population.We found rare 9/275 individuals (3.3%) (5 missense mutations 1 nonsense mutation leading premature stop codon), none present...
Brown-Vialetto-Van Laere syndrome (BVVLS) and Fazio-Londe disease (FLD) are rare neurological disorders presenting with pontobulbar palsy, muscle weakness respiratory insufficiency. Mutations in SLC52A2 (hRFVT-2) or SLC52A3 (hRFVT-3) genes can be responsible for these an autosomal recessive pattern of inheritance. The aim this study was to screen mutations among Indian families diagnosed BVVLS FLD.SLC52A2 were screened one FLD three patients by exon-specific amplification using PCR...
Summary Mutations in mitochondrial DNA cause severe multisystem disease, frequently associated with muscle weakness. The m.3243A>G mutation is the major of Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke Like episodes (MELAS). Experimental models that recapitulate disease phenotype vitro for modelling or drug screening are very limited. We have therefore generated hiPSC-derived fibres variable heteroplasmic mtDNA load without significantly affecting differentiation potential....
Protocol for the culture of WTC11 hPSCs harbouring a doxycycline-inducible Ngn2 system, differentiation this line into iNeurons and subsequent in N2B27 or BrainPhys medium.
Protocol for the culture of i3N-iNeurons in CytoView MEA 96-well plates and measurements electrical activity using Axion Biosystems Maestro Pro MEA.
Protocol for measurements of oxygen consumption rate (OCR) and extracellular acidifcation (ECAR) differentiated iNeurons using the Seahorse XF96 bioanalyser. describes simultaneous conduction XF Cell Mito Stress Test Real-Time ATP Rate Assay through made following automated sequential mitochondrial toxin additions. This protocol assumes each half a plate has same samples/conditions with Columns1-6 being used Columns7-12 Assay.
Protocol outlining establishment of a iNeuron hPSC line which stably expresses the mitoSRAI construct and differentiation, assessment lysosomal mitochondrial delivery in iNeurons.
Abstract Genetic variants conferring risk for Parkinson’s disease have been highlighted through genome-wide association studies, yet exploration of their specific mechanisms is lacking. Two candidate genes, KAT8 and KANSL1 , identified studies a PINK1-mitophagy screen, encode part the histone acetylating non-specific lethal complex. This complex localises to nucleus, where it has role in transcriptional activation, mitochondria, suggested mitochondrial transcription. In this study, we sought...
Abstract It has recently been shown that KAT8 , a genome-wide association study (GWAS) candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependant mitophagy. The encodes lysine acetyltransferase and represents the catalytically active subunit of non-specific lethal (NSL) epigenetic remodelling complex. In current study, we show contrary to KAT5 inhibition, dual inhibition via MG149 compound inhibits initial steps PINK1-dependant mitophagy process. More specifically,...