A5049262794- Neurogenetic and Muscular Disorders Research
- Neuroscience and Neuropharmacology Research
- Zebrafish Biomedical Research Applications
- Neurogenesis and neuroplasticity mechanisms
- Ion channel regulation and function
- RNA modifications and cancer
- RNA Research and Splicing
- Muscle Physiology and Disorders
- Nerve injury and regeneration
- Neuroscience of respiration and sleep
- Amyotrophic Lateral Sclerosis Research
- Photoreceptor and optogenetics research
- Neuroinflammation and Neurodegeneration Mechanisms
- Spinal Cord Injury Research
- Genetics and Neurodevelopmental Disorders
- Neurological disorders and treatments
- Neuroscience and Neural Engineering
- Neuroendocrine regulation and behavior
- Muscle activation and electromyography studies
- Cardiomyopathy and Myosin Studies
- Genetic Neurodegenerative Diseases
- Botulinum Toxin and Related Neurological Disorders
- Congenital Anomalies and Fetal Surgery
- Neural dynamics and brain function
- Vestibular and auditory disorders
Columbia University
2016-2025
Columbia University Irving Medical Center
2016-2021
McGill University
2020
Neurology, Inc
2015
National Institute of Neurological Disorders and Stroke
2001-2011
National Institutes of Health
2001-2011
Imperial College London
2000-2007
Wright State University
2005
University of Calgary
2002
University College London
1993-1995
Abstract Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms disease. loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant leads motor neuron degeneration, but neither has firmly established pathogenesis ALS. Here we characterize a series transgenic mouse lines that manifest progressive, mutant-dependent degeneration preceded by early, structural functional abnormalities at...
Highlights•C1q refines spinal sensory-motor circuits during normal development•Upregulated C1q tags SMA synapses for elimination via classical cascade and microglia•Pharmacological inhibition of or depletion microglia confer benefit in mice•C1q deletion results an excessive number synapses, leading to behavioral deficitsSummaryMovement is essential behavior requiring the assembly refinement motor circuits. However, mechanisms responsible circuit synapse maintenance are poorly understood....
Highlights•SMN deficiency induces early p53 activation in vulnerable SMA motor neurons•Inhibition of prevents neuron degeneration mice•p53S18 phosphorylation selectively marks degenerating neurons•Amino-terminal is required for degenerationSummaryThe hallmark spinal muscular atrophy (SMA), an inherited disease caused by ubiquitous the SMN protein, selective subsets neurons. Here, we show that cell-autonomous occurs but not resistant neurons mice at pre-symptomatic stages. Moreover,...
Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence developmentally immature motor neuron axons, many which actively degenerating. We identified similar features in a mouse model SMA,...
Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing genetically identified adult proprioceptors uncovered five molecularly distinct neuronal clusters. Validation cluster-specific transcripts in dorsal root ganglia skeletal demonstrates that two clusters correspond to MS GTO proprioceptors,...
Locomotion is a complex behavior required for animal survival. Vertebrate locomotion depends on spinal interneurons termed the central pattern generator (CPG), which generates activity responsible alternation of flexor and extensor muscles left right side body. It unknown whether multiple or single neuronal type control mammalian locomotion. Here, we show that ventral spinocerebellar tract neurons (VSCTs) drive generation maintenance locomotor in neonatal adult mice. Using mouse genetics,...
Mammalian spinal motoneurons are considered to be output elements of the cord that generate exclusively cholinergic actions on Renshaw cells, their intraspinal synaptic targets. Here, we show antidromic stimulation motor axons evokes depolarizing monosynaptic potentials in cells depressed, but not abolished, by antagonists. This residual potential was abolished 2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione. In presence antagonists, axon triggered locomotor-like...
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency in the survival motor neuron (SMN) protein. SMN mediates assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) and possibly other RNPs. Here, we investigated requirement for biogenesis function U7--an snRNP specialized 3'-end formation replication-dependent histone mRNAs that normally are not polyadenylated. We show impairs U7 decreases levels mammalian cells. The SMN-dependent reduction affects...
In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including SOD1-G93A mice, disassembly the neuromuscular synapse precedes motor neuron loss is sufficient to cause a decline in function that culminates lethal respiratory paralysis. We treated mice with an agonist antibody MuSK, receptor tyrosine kinase essential for maintaining synapses, determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The antibody, delivered after...
Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of neurons—a hallmark neurodegenerative disease spinal muscular atrophy (SMA)—through poorly understood mechanisms. Here, we show that function SMN assembly spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing Mdm2 and Mdm4, two nonredundant repressors p53. Decreased inclusion critical Mdm4 exons is most prominent SMA neurons correlates with both snRNP reduction p53 activation vivo....
During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis reduced spinal gap junctional coupling decreases temporally correlated activity that, in turn, modulates elimination, using mutant mice lacking connexin 40 (Cx40), a developmentally regulated junction protein expressed other neurons. In Cx40-/- mice, electrical among lumbar neurons, measured whole-cell...
The inhibitory action of glycine and GABA in adult neurons consists both shunting incoming excitations moving the membrane potential away from (AP) threshold. By contrast, immature neurons, postsynaptic potentials (IPSPs) are depolarizing; it is generally accepted that, despite their depolarizing action, these IPSPs because Cl(-) conductance increase. Here we investigated integration (dIPSPs) with excitatory inputs neonatal rodent spinal cord by means intracellular recordings lumbar...
Abstract The diversity of premotor interneurons in the mammalian spinal cord is generated from a few phylogenetically conserved embryonic classes (V0, V1, V2, V3). Their mechanisms diversification remain unresolved, although these are clearly important to understand motor circuit assembly cord. Some Ia inhibitory (IaINs) and all Renshaw cells (RCs) derive V1 interneurons; however, adult they display distinct functional properties synaptic inputs, for example proprioceptive inputs...
Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, receptor tyrosine kinase. Lrp4 can bind stimulate strongly suggesting association between independent additional ligands, initiates mice. zebrafish, Wnts, which Frizzled (Fz)-like domain required for prepatterning, Wnts may contribute to neuromuscular development mammals. We show mice but not MuSK Fz-like...
Reduced expression of the survival motor neuron (SMN) protein causes neurodegenerative disease spinal muscular atrophy (SMA). Here, we show that adeno-associated virus serotype 9 (AAV9)-mediated delivery Stasimon—a gene encoding an endoplasmic reticulum (ER)-resident transmembrane regulated by SMN—improves function in a mouse model SMA through multiple mechanisms. In proprioceptive neurons, Stasimon overexpression prevents loss afferent synapses on neurons and enhances sensory-motor...