A5017458937- Lysosomal Storage Disorders Research
- Cellular transport and secretion
- Glycogen Storage Diseases and Myoclonus
- Trypanosoma species research and implications
- Adenosine and Purinergic Signaling
- Child Nutrition and Feeding Issues
- Congenital gastrointestinal and neural anomalies
- RNA regulation and disease
- Neuroinflammation and Neurodegeneration Mechanisms
- Calcium signaling and nucleotide metabolism
- Retinal Development and Disorders
- Neurogenetic and Muscular Disorders Research
- Autophagy in Disease and Therapy
- Spinal Dysraphism and Malformations
- Cytomegalovirus and herpesvirus research
- Glioma Diagnosis and Treatment
- Galectins and Cancer Biology
- Autism Spectrum Disorder Research
- Carbohydrate Chemistry and Synthesis
- Retinopathy of Prematurity Studies
- Cannabis and Cannabinoid Research
- Anesthesia and Neurotoxicity Research
- Sphingolipid Metabolism and Signaling
- Clusterin in disease pathology
- Biochemical Acid Research Studies
Washington University in St. Louis
2019-2025
University College London
2022-2024
Research Network (United States)
2023
National Hospital for Neurology and Neurosurgery
2023
Pediatrics and Genetics
2023
Universidad de Londres
2023
University of London
2023
UCLA Medical Center
2017-2021
Harbor–UCLA Medical Center
2017-2021
King's College London
2013-2020
Abstract Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification actionable targets is urgently needed. Here we identify a pharmacologically pathway that controls clearance via Akt modulation transcription factor EB (TFEB), master regulator lysosomal pathways. We show phosphorylates TFEB at Ser467 and represses nuclear translocation independently mechanistic target rapamycin complex 1...
Significance Infantile neuronal ceroid lipofuscinosis (INCL, or infantile Batten disease) is a fatal childhood disease that devastates the brain. Trying to treat brain alone has so far proved ineffective, we looked for effects of in other parts body. Unexpectedly, found spinal cord severely affected before and contributes outcome. Directing gene therapy just INCL mice can improve their disease. However, treating both provides most effective therapeutic strategy ever seen this This combined...
Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression the core clock gene Bmal1 has been described in patients with PD. BMAL1 required for circadian function but also serves nonrhythmic functions. Germline deletion can cause brain oxidative stress synapse loss mice, it exacerbate dopaminergic neurodegeneration response to toxin MPTP. Here we examined effect cell type-specific on neuron viability vivo. We observed that global, postnatal caused...
The neuronal ceroid lipofuscinoses are fatal neurodegenerative disorders in which the visual system is affected early disease progression. A typical accompanying feature neuroinflammation, pathogenic impact of presently obscure. Here we investigated role inflammatory cells palmitoyl protein thioesterase 1-deficient (Ppt1-/-) mice, a model infantile lipofuscinosis (CLN1 disease, infantile), predominantly focusing on system. We detected an infiltration CD8+ T-lymphocytes and observed...
Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons the enteric nervous system (ENS), master regulator bowel function. To test hypothesis, we evaluated mouse models neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 CLN2 disease, respectively), lysosomal storage disorders caused by deficiencies palmitoyl protein thioesterase-1 tripeptidyl peptidase-1,...
Juvenile neuronal ceroid lipofuscinosis (JNCL or CLN3 disease) is an autosomal recessive lysosomal storage disease resulting from mutations in the gene that encodes a membrane protein. The primarily affects brain with widespread intralysosomal accumulation of autofluorescent material and fibrillary gliosis, as well loss specific populations. As experimental treatment for CNS manifestations JNCL, we have developed serotype rh.10 adeno-associated virus vector expressing human cDNA...
Parkinson's disease (PD) affects millions of people worldwide, and up to 40% these patients develop dementia, profoundly affecting their quality life. Whether dementia (PDD) simply represents a late stage PD or constitutes distinct neurodegenerative process remains unresolved. To clarify this, we generated the largest single nuclear transcriptomic atlas PDD date - almost one million nuclei derived from anterior cingulate cortex inferior parietal lobule 64 post-mortem donors. By integrating...
Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, anti-seizure effects. Here, we determined the effects of chronic CBD administration in mouse model CLN1 disease (Cln1-/-) that simultaneously exhibits neuroinflammation, neurodegeneration, spontaneous seizures. Proteomic analysis showed putative receptors are expressed at similar levels brains Cln1-/- mice compared normal animals. received an oral dose (100 mg/kg/day) for...
Niemann–Pick disease type C1 (NP-C) is a prematurely lethal genetic lysosomal storage disorder with neurological and visceral pathology resulting from mutations in the NPC1 gene encoding transmembrane protein NPC1. There currently no cure for NP-C, only modifying treatment, miglustat, slows progression but does not significantly attenuate symptoms. AAV-mediated therapy an attractive option due to large size of human gene, there may be packaging truncation issues during vector manufacturing....
Abstract Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) sulfatide their toxic metabolites psychosine lysosulfatide, respectively. We discovered a potent selective small molecule inhibitor (S202) ceramide galactosyltransferase (CGT), key enzyme for GalCer biosynthesis, characterized its use as substrate reduction therapy (SRT). Treating KD mouse model with S202 dose-dependently reduced in central (CNS)...
Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development more effective and persistent therapies. Here, we investigated nature progression neurological underlying neuropathological changes in Cln2R207X mice, which carry one most common pathogenic mutations human patients but are yet to be fully characterized. Long-term electroencephalography recordings...
Aim To understand the progression of CLN1 disease and develop effective therapies we need to characterize early sites pathology. Therefore, performed a comprehensive evaluation nature timing pathology in spinal cord, which appears especially vulnerable, how this may affect behaviour. Methods We measured volume neuronal number, quantified glial activation, lymphocyte infiltration oligodendrocyte maturation, as well cytokine profile analysis during stages Ppt1‐deficient ( Ppt1 −/− ) mouse...
Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss motor function. Recently, we reported the use an AAV9-mediated gene therapy that prevents progression in mouse model CLN6-Batten (Cln6nclf), restoring lifespans treated animals. Despite success our viral-mediated therapy, dosing strategy was optimized for delivery to brain parenchyma may limit therapeutic potential other disease-relevant tissues, such as eye. Here,...
CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or Batten is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the gene encoding soluble enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for disease have proven challenging because of aggressive course and need to treat widespread areas brain spinal cord. Indeed, therapy has less effective than other similar deficiencies. We therefore tested efficacy replacement (ERT) by...
In utero hematopoietic cell transplantation (IUHCT) utilizes fetal immune tolerance to achieve durable chimerism without conditioning or immunosuppression during a unique window in development. Though donor cells have been observed within the nervous system following injection, timeline and distribution of cellular trafficking across blood-brain barrier IUHCT is not well understood. We injected 20 × 106 adult bone marrow mononuclear intravenously at gestational age (GA) 12–17 days found that...
The Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation.We have tested this comparing known differences in symptomatology pathology of CLN1 phenotype...
Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, characterised devastating neuropathology death during infancy. In this study, we investigated benefit of systemically delivered AAV9 vectors expressing human gene at two different doses comparing a neuronal-selective promoter ubiquitous...
Abstract CLN1 disease is a fatal inherited neurodegenerative lysosomal storage of early childhood, caused by mutations in the gene, which encodes enzyme Palmitoyl protein thioesterase-1 (PPT-1). We recently found significant spinal pathology Ppt1-deficient ( Ppt1 −/− ) mice and human that contributes to clinical outcome precedes onset brain pathology. Here, we quantified this at 3 7 months age revealing progressive glial activation vulnerability interneurons. Tandem mass tagged proteomic...
Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal degradation glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), fusion protein comprised recombinant human NAGLU modified insulin-like growth factor 2, development as an...