A5064623876- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Neuroscience and Neural Engineering
- RNA and protein synthesis mechanisms
- Nerve injury and regeneration
- 3D Printing in Biomedical Research
- Alzheimer's disease research and treatments
- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Genetic Neurodegenerative Diseases
- Prion Diseases and Protein Misfolding
- Receptor Mechanisms and Signaling
- Synthetic Organic Chemistry Methods
- Parkinson's Disease Mechanisms and Treatments
- Neurological diseases and metabolism
- Metabolism and Genetic Disorders
- Pharmacological Receptor Mechanisms and Effects
Tel Aviv University
2017-2023
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons ~95% amyotrophic lateral sclerosis (ALS) patients, but contribution axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show accumulation intra-muscular nerves from ALS patients and axons human iPSC-derived patient, as well neuromuscular junctions (NMJs) a mislocalization mouse model. In axons, hyper-phosphorylated promotes G3BP1-positive ribonucleoprotein (RNP) condensate...
Amyotrophic lateral sclerosis (ALS) is a multifactorial lethal motor neuron disease with no known treatment. Although the basic mechanism of its degenerative pathogenesis remains poorly understood, subcellular spatial alteration in RNA metabolism thought to play key role. The nature these RNAs elusive, and comprehensive characterization axonal involved maintaining neuronal health has yet be described. Here, using cultured spinal cord (SC) neurons grown compartmented platform followed by...
Abstract Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations axonal transport (AT), formation of toxic protein aggregates Neuromuscular Junction (NMJ) disruption, which all lead to degeneration neuron death. Pridopidine small molecule that has been clinically developed for Huntington disease. Here we tested...
Local protein synthesis in neuronal axons plays an important role essential spatiotemporal signaling processes; however, the molecular basis for post-transcriptional regulation controlling this process is still not fully understood. Here we studied axonal mechanisms underlying transport and localization of microRNA (miRNA) RNAi machinery along axon. We first identified miRNAs, Dicer, Argonaute-2 (Ago2) motor neuron (MN) axons. then demonstrated that mitochondria associate with miR-124...
Nuclear-encoded mitochondrial protein mRNAs have been found to be localized and locally translated within neuronal processes. However, the mechanism of transport for those distal locations is not fully understood. Here, we describe axonal co-transport Cox7c with mitochondria. Fractionation analysis single-molecule fluorescence in situ hybridization (smFISH) assay revealed that endogenous mRNA encoding was preferentially associated mitochondria a mouse cell line primary motor neuron axons,...
Tropomyosin-related tyrosine kinase B (TrkB) is the receptor for brain-derived neurotrophic factor (BDNF) and provides critical signaling that supports development function of mammalian nervous system. Like other kinases (RTKs), TrkB thought to signal as a dimer. Using cell imaging biochemical assays, we found acted monomeric at plasma membrane regardless its binding BDNF initial activation. Dimerization occurred only after internalization accumulation monomers within BDNF-containing...
The neuromuscular junction (NMJ) is the largest, most-complex synapse in human body. Motor neuron (MN) diseases, such as amyotrophic lateral sclerosis (ALS), specifically target MNs and NMJs. However, little known about reasons for MN-selective neuronal synaptic vulnerability MN diseases. Here, utilizing a compartmental microfluidic vitro co-culture system, we provide possible explanation why NMJ, other than its unusual dimensions, differs from synapses. By using live-imaging techniques,...
Amyotrophic lateral sclerosis (ALS) is a fatal non-cell-autonomous neurodegenerative disease characterized by the loss of motor neurons (MNs). Mutations in CRMP4 are associated with ALS patients, and elevated levels suggested to affect MN health SOD1G93A -ALS mouse model. However, mechanism which mediates toxicity MNs poorly understood. Here, using tissue from human patients sporadic ALS, derived C9orf72-mutant model, we demonstrate that subcellular changes promote ALS. First, show while...
Motor neurons (MNs) are highly polarized cells with very long axons. Axonal transport is a crucial mechanism for MN health, contributing to neuronal growth, development, and survival. We describe detailed method the use of microfluidic chambers (MFCs) tracking axonal fluorescently labeled organelles in This rapid, relatively inexpensive, allows monitoring intracellular cues space time. step by protocol for: 1) Fabrication polydimethylsiloxane (PDMS) MFCs; 2) Plating ventral spinal cord...
Motor neurons (MNs) are highly polarized cells with very long axons. Axonal transport is a crucial mechanism for MN health, contributing to neuronal growth, development, and survival. We describe detailed method the use of microfluidic chambers (MFCs) tracking axonal fluorescently labeled organelles in This rapid, relatively inexpensive, allows monitoring intracellular cues space time. step by protocol for: 1) Fabrication polydimethylsiloxane (PDMS) MFCs; 2) Plating ventral spinal cord...
Abstract Localized protein synthesis plays a key role in spatiotemporal regulation of the cellular proteome. Neurons, which extend axons over long distances, heavily depend on this process. However, mechanisms by axonal mRNAs are transported to target sites not fully understood. Here, we describe novel for mitochondria shuttling nuclear encoded mRNA along axons. Fractionation analysis and smFISH revealed that encoding Cox7c is preferentially associated with from neuronal cell line primary...
Motor neurons are highly polarized cells, with long axons that extend to more than 1 m in the adult human. The further arborize into a specialized synaptic compartment, motor unit, containing up 2000 neuromuscular junctions (NMJs). While size of other neuronal synapses can be µm, NMJ is much larger and reach 10–30 µm (Jones et al., 2017). vast unit requires evolutionally adapt supply this distal portion sufficient amount ATP, as well replenish axonal protein pool order maintain their...
Abstract Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons ~95% ALS patients, but contribution axonal TDP-43 to this fatal neurodegenerative disease is unclear. Here, we find accumulation axons intra-muscular nerves from and neuromuscular junctions (NMJs) a mouse model with mislocalization. This leads formation G3BP1- TDP-43- positive RNA-granules neuron axons, inhibition local protein synthesis NMJs. Specifically, synaptic levels...