A5075796844- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Autophagy in Disease and Therapy
- Ubiquitin and proteasome pathways
- Alzheimer's disease research and treatments
- Phosphodiesterase function and regulation
- Amyotrophic Lateral Sclerosis Research
- Neuroscience and Neuropharmacology Research
- Protein Kinase Regulation and GTPase Signaling
- Endoplasmic Reticulum Stress and Disease
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- PI3K/AKT/mTOR signaling in cancer
- Receptor Mechanisms and Signaling
- Molecular Biology Techniques and Applications
- Parkinson's Disease Mechanisms and Treatments
- Cholinesterase and Neurodegenerative Diseases
- Nerve injury and regeneration
- Redox biology and oxidative stress
- Ion channel regulation and function
- Genetics and Neurodevelopmental Disorders
- Cancer-related Molecular Pathways
- Prion Diseases and Protein Misfolding
- Nitric Oxide and Endothelin Effects
- Cell death mechanisms and regulation
Scripps Research Institute
2013-2024
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2024
Johns Hopkins Medicine
2010-2019
Johns Hopkins University
2008-2019
Institute of Behavioral Sciences
2013-2016
Heidelberg University
2006-2014
National Institute of Mental Health and Neurosciences
1995-2010
Osnabrück University
2002-2006
In patients with Huntington's disease (HD), the protein huntingtin (Htt) has an expanded polyglutamine (poly-Q) tract. HD results in early loss of medium spiny neurons striatum, which impairs motor and cognitive functions. Identifying physiological role molecular functions Htt may yield insight into pathogenesis. We found that promotes signaling by mTORC1 [mechanistic target rapamycin (mTOR) complex 1] this is potentiated poly-Q-expanded Htt. Knocking out mouse embryonic stem cells or human...
Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine huntingtin (mHTT). mHTT ubiquitously present, but it induces noticeable damage to brain's striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal progression HD are associated with inflammatory response; however, underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, critical regulator autophagy responses in HD....
Abstract The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling suppresses protein synthesis in mouse HD striatal neuronal cells. Depletion enhances increases speed ribosomal translocation, while directly inhibits vitro. Fmrp, a known regulator stalling, is upregulated HD, its depletion has no discernible effect on or We interactions proteins translating...
Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted studies a model for neuropsychiatric illness using transgenic mice expressing putative dominant-negative disrupted schizophrenia 1 (DN-DISC1). We detected marked augmentation GAPDH–seven absentia homolog Siah protein binding DISC1 mice, major hallmark nuclear GAPDH cascade that is activated response to oxidative stress. Furthermore, deficits were observed...
The neurotrophin receptor p75(NTR) has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction pathologic states, there is limited understanding of mechanisms that regulate expression injury. Here, we show focal cerebral ischemia vivo or oxygen-glucose deprivation organotypic hippocampal slices neurons, rapidly induced. A concomitant proNGF, a ligand for p75(NTR), also observed. Induction this ligand/receptor system pathologically relevant, as...
The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as progresses. However, underlying mechanisms neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification mHtt promotes cellular toxicity, but in vivo role functions HD pathogenesis Here, we report deletion Q175DN HD-het...
Significance Damaged mitochondria are eliminated by lysosomes, a process called mitophagy. However, the brain tissue specific roles and mechanisms of mitophagy remain unknown. We report that Rhes, protein highly enriched in striatum, eliminates damaged via mitophagy, function may regulate optimum number striatum. when irreversibly damaged, as presence 3-NP (an inhibitor complex II, SDH), Rhes exacerbates association with Nix, receptor promotes cell death. Intriguingly, can travel membranous...
Abstract Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to via formation of tunneling-like nanotubes (TNTs). However, mechanisms by which mediates diverse remain unclear. is small GTPase family member contains unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain promotes SUMO post-translational modification proteins (SUMOylation)...
Extracellular signal-regulated kinase (ERK) activation has been shown to promote neuronal death in various paradigms. We demonstrated previously that the late and sustained ERK cerebellar granule neurons (CGNs) cultured low potassium predominantly promotes plasma membrane (PM) damage. Here, we examined effects of a well established survival factor, insulin-like growth factor 1 (IGF-1), on cell pathway. Stimulation CGNs with IGF-1 induced an early transient but abrogated appearance ERK....
Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations amyloid beta, and intracellular fibrils containing hyperphosphorylated tau. Tau mutations familial tauopathies confirmed a central role tau pathology; however, the alteration sequence tau-dependent neurodegeneration AD remain elusive. Using Sindbis virus-mediated expression AD-relevant constructs hippocampal slices, we show that disease-like modifications affect...
Rheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of synthesis also physiologically regulated. Thus, with cell stress, the unfolded response system leads phosphorylation initiation factor eIF2α arrest We now demonstrate major role for Rheb in inhibiting by enhancing kinase-like ER kinase (PERK). Interplay between stimulatory inhibitory roles may enable cells modulate varying environmental stresses.
A novel molecular target that signals abnormal involuntary movement in Parkinson’s disease treatment is discovered.