A5062583689- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Alzheimer's disease research and treatments
- Neurotransmitter Receptor Influence on Behavior
- Neurogenetic and Muscular Disorders Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetic Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Tryptophan and brain disorders
- Extracellular vesicles in disease
- Stress Responses and Cortisol
- Neuroscience and Neuropharmacology Research
- Autophagy in Disease and Therapy
- Attention Deficit Hyperactivity Disorder
- Memory and Neural Mechanisms
- Neuroendocrine regulation and behavior
- Cholinesterase and Neurodegenerative Diseases
- Amino Acid Enzymes and Metabolism
- Genetics, Aging, and Longevity in Model Organisms
- Immune cells in cancer
- Dementia and Cognitive Impairment Research
- Botulinum Toxin and Related Neurological Disorders
- Neurogenesis and neuroplasticity mechanisms
- Nicotinic Acetylcholine Receptors Study
- Cell Adhesion Molecules Research
University of Alabama at Birmingham
2015-2024
Duke University Hospital
2010-2015
Duke Medical Center
2010-2015
Duke University
2012-2014
Loss-of-function mutations in progranulin, a lysosomal glycoprotein, cause neurodegenerative disease. Progranulin haploinsufficiency causes frontotemporal dementia (FTD) and complete progranulin deficiency CLN11 neuronal ceroid lipofuscinosis (NCL). replacement is rational therapeutic strategy for these disorders, but there are critical unresolved mechanistic questions about gene therapy approach, including its potential to reverse existing pathology. Here, we address issues using an AAV...
Frontotemporal dementia (FTD) is the most common cause of in people under 60 yr age and pathologically associated with mislocalization TAR DNA/RNA binding protein 43 (TDP-43) approximately half cases (FLTD-TDP). Mutations gene encoding progranulin (GRN), which lead to reduced levels, are a significant familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 neurodegeneration. Here, we report retinal thinning early disease phenotype humans GRN mutations that...
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets clinically available drugs lacking. Here, we report that protein of the Rho-associated kinases (ROCK1 ROCK2), p70 S6 kinase (S6K), mammalian target rapamycin (mTOR) were increased in PSP CBD brains. RNAi depletion ROCK1 or ROCK2 reduced mRNA level human...
Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known genotoxins neurotoxins cause mtDNA damage, depletion, neurodegeneration in Caenorhabditis elegans. found that paraquat, cadmium chloride aflatoxin B1 caused more than nuclear paraquat also dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) similar levels damage. To further test whether could be...
Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are common autosomal dominant cause of frontotemporal dementia, neurodegenerative disease commonly characterized disrupted social emotional behaviour. GRN thought to dementia through haploinsufficiency, therefore, boosting expression from the intact allele is rational treatment strategy. However, this approach has not been tested an animal model it unclear if could correct...
Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical defects that define PD, up 80% of patients experience cognitive changes psychiatric disturbances, referred PD dementia (PDD). Pathologically, characterized loss dopaminergic neurons in substantia nigra pars compacta (SNpc) intracellular inclusions, called Lewy bodies neurites, composed mostly α-synuclein. Much research has focused on...
Abstract Loss-of-function mutations in progranulin ( GRN ) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic result haploinsufficiency, which is thought to dementia mutation carriers. Progranulin haploinsufficiency may drive pathogenesis by disrupting lysosomal function, as patients with on both alleles develop the storage disorder neuronal ceroid lipofuscinosis, and (FTD- also accumulate lipofuscin. The specific deficits caused insufficiency remain unclear,...
Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction PGRN and lead to development of frontotemporal dementia (FTD-GRN). is secreted lysosomal chaperone, immune regulator, neuronal survival factor that shuttled lysosome through multiple receptors, including sortilin. Here, we report characterization latozinemab, human monoclonal antibody decreases levels sortilin, which expressed on myeloid cells shuttles for degradation, blocks its interaction with...
Acute tryptophan depletion (ATD) is a method of lowering brain serotonin (5-HT). Administration large neutral amino acids (LNAA) limits the transport endogenous (TRP) across blood barrier by competition with other LNAAs and subsequently decreases serotonergic neurotransmission. A recent discussion on specificity efficacy ATD paradigm for inhibition central nervous 5-HT has arisen. Moreover, side effects such as vomiting nausea after intake (AA) still limit its use. Moja-De revised mixture...
Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), neurodegenerative disorder which social behavior is disrupted. Progranulin-insufficient mice, both Grn(+/-) and Grn(-/-) , used as models FTD due to GRN mutations, with mice mimicking the haploinsufficiency patients mutations. have increased dominance tube test at 6 months age, although this phenotype has not been reported mice. In study, we investigated how...
Most life-long drug addiction begins during adolescence. Important structural and functional changes in brain occur adolescence developmental differences forebrain dopamine systems could mediate a biologic vulnerability to Studies investigating age psychostimulant responses have yielded mixed results, possibly because of different mechanisms for increasing extracellular dopamine. Recent research from our laboratory suggests that adolescent may be most affected by selective uptake inhibitors....
Loss of function mutations in progranulin (GRN) are a major cause frontotemporal dementia (FTD). Progranulin is secreted glycoprotein that localizes to lysosomes and critical for proper lysosomal function. Heterozygous GRN mutation carriers develop FTD with TDP-43 pathology exhibit signs dysfunction the brain, increased levels proteins lipofuscin accumulation. Homozygous neuronal ceroid lipofuscinosis (NCL), an earlier-onset storage disorder caused by severe dysfunction. Multiple genome-wide...
Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD), possibly due to loss progranulin's neurotrophic and anti-inflammatory effects. Progranulin promotes neuronal growth protects against excitotoxicity other forms injury. It is unclear if these effects mediated through cellular signaling or promotion lysosomal function. secreted proprotein that may activate cell-surface receptors. However, efficiently trafficked lysosomes necessary for...
Abstract Loss of function progranulin ( GRN ) mutations are a major autosomal dominant cause frontotemporal dementia (FTD). Patients with FTD due to (FTD- develop lobar degeneration TDP-43 pathology type A (FTLD-TDP A) and exhibit elevated levels lysosomal proteins storage material in frontal cortex, perhaps indicating dysfunction as mechanism disease. To investigate whether patients sporadic FTLD similar signs dysfunction, we compared protein levels, transcript FTD- or FTLD-TDP A. We...
Diet and nutrition can impact on the biological processes underpinning neuropsychiatric disorders. Amino acid (AA) mixtures lacking a specific neurotransmitter precursor change levels of brain serotonin (5-HT) or dopamine (DA) in central nervous system. The availability these substances within is determined by blood-brain barrier (BBB) that restricts access peripheral AA into brain. tryptophan (TRP) compete with endogenous TRP for uptake across BBB, which turn leads to decrease 5-HT...
Abstract Extracellular vesicles (EVs) are secreted by all major cell types of the brain, providing a mode intercellular communication and pathway for disposal cellular debris. EVs help maintain healthy brain function, but may also contribute to diseases affecting brain. might aging as aging‐related processes such inflammation senescence alter EV cargo, promoting further senescence. However, effects on function in remain poorly understood. To address this question, we measured levels protein...
Abstract Objective The goal of this study was to investigate the effect progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population that may contribute progression neurodegenerative disease. Loss‐of‐function mutations in ( GRN ) are major cause frontotemporal dementia (FTD), and brains from carriers with FTD (FTD‐ exhibit signs lysosomal dysfunction. Lysosomal dysfunction induce compensatory increases secretion exosomes, EVs secreted endolysosomal system, so we...
Loss-of-function mutations in progranulin (GRN) are one of the most common genetic causes frontotemporal dementia (FTD), a progressive, fatal neurodegenerative disorder with no available disease-modifying treatments. Through haploinsufficiency, these reduce levels progranulin, protein that has neurotrophic and anti-inflammatory effects. Increasing expression from intact allele is therefore potential approach for treating individuals GRN mutations. Based on well-known effects physical...