A5033083330- Heat shock proteins research
- Endoplasmic Reticulum Stress and Disease
- Prion Diseases and Protein Misfolding
- Nerve injury and regeneration
- Protein Structure and Dynamics
- Mitochondrial Function and Pathology
- Signaling Pathways in Disease
- Alzheimer's disease research and treatments
- Sirtuins and Resveratrol in Medicine
- Microtubule and mitosis dynamics
- Neurogenesis and neuroplasticity mechanisms
- Amyotrophic Lateral Sclerosis Research
- Autophagy in Disease and Therapy
- Computational Drug Discovery Methods
- Genetics, Aging, and Longevity in Model Organisms
- Immune Response and Inflammation
- Enzyme Structure and Function
- Neurological diseases and metabolism
- Antimicrobial Peptides and Activities
- Advanced Combinatorial Mathematics
- Genetic Neurodegenerative Diseases
- Biochemical effects in animals
- Vitamin C and Antioxidants Research
- Transgenic Plants and Applications
- Retinal Diseases and Treatments
University of Iowa
2019-2025
Washington University in St. Louis
2016-2019
Hope Center for Neurological Disorders
2015
Pediatrics and Genetics
2013-2014
University of North Carolina at Chapel Hill
2008-2013
Indiana University School of Medicine
2009
Icahn School of Medicine at Mount Sinai
2006
Axon degeneration is an evolutionarily conserved pathway that eliminates damaged or unneeded axons. Manipulation of this poorly understood may allow treatment a wide range neurological disorders. In RNAi-based screen performed in cultured mouse DRG neurons, we observed strong suppression injury-induced axon upon knockdown Sarm1 [SARM (sterile α-motif-containing and armadillo-motif containing protein)]. We find SARM-dependent program engaged by disparate neuronal insults: SARM ablation blocks...
Mitochondrial dysfunction is the underlying cause of many neurological disorders, including peripheral neuropathies. Mitochondria rely on a proton gradient to generate ATP and interfering with electron transport chain function can lead deleterious accumulation reactive oxygen species (ROS). Notably, loss mitochondrial potential precedes cellular demise in several programmed cell destruction pathways, axons undergoing Wallerian degeneration. Here, we demonstrate that depolarization triggers...
Injury-induced (Wallerian) axonal degeneration is regulated via the opposing actions of pro-degenerative factors such as SARM1 and a MAPK signal pro-survival factors, most important which NAD+ biosynthetic enzyme NMNAT2 that inhibits activation pathway. Here we investigate mechanism by signaling facilitates degeneration. We show promotes turnover survival factor in cultured mammalian neurons well Drosophila ortholog dNMNAT motoneurons. The increased levels are required for protection caused...
Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner this degeneration cascade, also known as Wallerian degeneration; however, mechanism SARM1-dependent neuronal destruction still obscure. SARM1 possesses TIR domain necessary for activity. In other proteins, dimerized...
Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection models disease, suggesting that inhibiting SARM1 a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist target SARM1. We, therefore, developed dominant-negatives potently block cellular axotomy neuropathy. To assess efficacy vivo, we...
Transcription errors occur in all living cells; however, it is unknown how these affect cellular health. To answer this question, we monitor yeast cells that are genetically engineered to display error-prone transcription. We discover suffer from a profound loss proteostasis, which sensitizes them the expression of genes associated with protein-folding diseases humans; thus, transcription represent new molecular mechanism by can acquire disease phenotypes. further find error rate increases...
Neurotrophic factors are critical for establishing functional connectivity in the nervous system and sustaining neuronal survival through adulthood. As first neurotrophic factor purified, nerve growth (NGF) is extensively studied its prolific role axon outgrowth, pruning, survival. Applying NGF to diseased tissue an exciting therapeutic option understanding how regulates local susceptibility pathological degeneration exploiting full potential. Our study identifies surprising connections...
Mechanisms for cooperation between the cytosolic Hsp70 system and ubiquitin proteasome during protein triage are not clear. Herein, we identify new mechanisms selection of misfolded proteins degradation via defining functional interactions specific Hsp70/Hsp40 pairs quality control ligases. These studies revolved around use S. cerevisiae to elucidate pathway a terminally reporter protein, short-lived GFP (slGFP). The Type I Hsp40 Ydj1 acts with suppress slGFP aggregation. In contrast, II...
Axon degeneration is a prominent event in many neurodegenerative disorders. injury stimulates an intrinsic self-destruction program that culminates activation of the prodegeneration factor SARM1 and local dismantling damaged axon segments. In healthy axons, activity restrained by constant delivery survival NMNAT2. Elevating NMNAT2 neuroprotective, while loss evokes SARM1-dependent degeneration. As gatekeeper survival, abundance important regulatory node neuronal health, highlighting need to...
Axon integrity is essential for functional connectivity in the nervous system. The degeneration of stressed or damaged axons a common and sometimes initiating event neurodegenerative disorders. Stathmin-2 (Stmn2) an axon maintenance factor that depleted amyotrophic lateral sclerosis, replenishment Stmn2 can restore neurite outgrowth diseased neurons. However, mechanisms responsible Stmn2-mediated injured neurons are not known. We used primary sensory to interrogate role severed axons....
Type I Hsp40s are molecular chaperones that protect neurons from degeneration by modulating the aggregation state of amyloid-forming proteins. How recognize β-rich, amyloid-like substrates is currently unknown. Thus, we examined mechanism for binding between Hsp40 Ydj1 and yeast prion [RNQ+]. recognized Gln/Asn-rich domain Rnq1 specifically when it assembled into [RNQ+] state. Upon deletion YDJ1, overexpression killed yeast. Surprisingly, suppression toxicity was dependent upon farnesylation...
Glaucoma is one of the leading causes irreversible blindness worldwide and vision loss in disease results from deterioration retinal ganglion cells (RGC) their axons. Metabolic dysfunction RGC plays a significant role onset progression both human patients rodent models, highlighting need to better define mechanisms regulating cellular energy metabolism glaucoma. This study sought determine if Sarm1, gene involved axonal degeneration NAD+ metabolism, contributes glaucomatous mouse model with...
ABSTRACT Neurotrophic factors are critical for establishing functional connectivity in the nervous system and sustaining neuronal survival through adulthood. As first neurotrophic factor purified, nerve growth (NGF) is extensively studied its prolific role axon outgrowth, pruning, survival. Applying NGF to diseased tissue an exciting therapeutic option understanding how regulates local susceptibility pathological degeneration exploiting full potential. Our study identifies surprising...
Protein aggregation is a hallmark of large and diverse number conformational diseases. Molecular chaperones the Hsp40 family ( Escherichia coli DnaJ homologs) recognize misfolded disease proteins suppress accumulation toxic protein species. Type I Hsp40s are very potent at suppressing facilitating refolding damaged proteins. Yet, molecular mechanism for recognition nonnative polypeptides by such as yeast Ydj1 not clear. Here we computationally identify unique motif that selectively...
Onset of proteotoxicity is linked to change in the subcellular location proteins that cause misfolding diseases. Yet, factors drive changes disease protein localization and impact residence new surroundings on are not entirely clear. To address these issues, we examined aspects caused by Rnq1-green fluorescent (GFP) a huntingtin's exon-1 fragment with an expanded polyglutamine tract (Htt-103Q), which dependent upon intracellular presence [RNQ+] prions. Increasing heat-shock 40 chaperone...
Programmed axon degeneration (AxD) is a key feature of many neurodegenerative diseases. In healthy axons, the survival factor NMNAT2 inhibits SARM1, central executioner AxD, preventing it from initiating rapid local NAD+ depletion and metabolic catastrophe that precipitates destruction. Because these components AxD pathway act within neurons, was also assumed timetable set strictly by cell-intrinsic mechanism independent neuron-extrinsic processes later activated fragmentation. However,...