A5000714443- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Nerve injury and regeneration
- Alzheimer's disease research and treatments
- Neurogenesis and neuroplasticity mechanisms
- Prion Diseases and Protein Misfolding
- Hereditary Neurological Disorders
- Axon Guidance and Neuronal Signaling
- Neurological diseases and metabolism
- Neuroscience and Neural Engineering
- Autophagy in Disease and Therapy
- Ubiquitin and proteasome pathways
- Parkinson's Disease Mechanisms and Treatments
- Genetic Neurodegenerative Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Cholinesterase and Neurodegenerative Diseases
- Genetics and Neurodevelopmental Disorders
- Muscle activation and electromyography studies
- biodegradable polymer synthesis and properties
- RNA Interference and Gene Delivery
- Histone Deacetylase Inhibitors Research
- Neuroscience and Neuropharmacology Research
- Biochemical Acid Research Studies
- Fungal and yeast genetics research
- 14-3-3 protein interactions
Northwestern University
2016-2025
Cancer Research Center
2012-2023
Turner Consulting Group (United States)
2019
Les Turner ALS Foundation
2012-2018
Alzheimer’s Disease Neuroimaging Initiative
2018
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
2012-2016
Indo-American Center
2012
Harvard University
2006-2011
Harvard Stem Cell Institute
2006
Massachusetts General Hospital
2006
The misfolding of the prion protein (PrP c ) is a central event in diseases, yet normal function PrP remains unknown. has putative roles many cellular processes including signaling, survival, adhesion, and differentiation. Given abundance developing mature mammalian CNS, we investigated role neural development adult neurogenesis, which occurs constitutively dentate gyrus (DG) hippocampus olfactory bulb from precursors subventricular zone (SVZ)/rostral migratory stream. In vivo , find that...
Amyotrophic lateral sclerosis (ALS) is characterized by predominant vulnerability and central degeneration of both corticospinal/corticobulbar motor neurons (CSMN; “upper neurons”) in cerebral cortex, spinal/bulbar (SMN; “lower spinal cord brainstem. Increasing evidence indicates broader cortex pathology cognitive, sensory, association systems select cases. It remains unclear whether widely accepted transgenic ALS models, particular hSOD1 G93A mice, undergo CSMN molecularly/developmentally...
Abstract Apical dendrites of Betz cells are important sites for the integration cortical input, however their health has not been fully assessed in ALS patients. We investigated primary motor cortices isolated from post-mortem normal control subjects, patients with familial (fALS), sporadic (sALS), frontotemporal dementia (FTD-ALS), and Alzheimer’s disease (AD), found profound apical dendrite degeneration both fALS sALS, as well FTD-ALS In contrast, AD controls retain cellular integrity...
Epac2 disruption impairs basal (but not apical) dendrite complexity in cortical neurons, and an autism-associated mutation implicates a Ras/Epac2 signaling pathway the active maintenance of dendritic arbors.
The recent identification of profilin1 mutations in 25 familial ALS cases has linked altered function this cytoskeleton-regulating protein to the pathogenesis motor neuron disease. To investigate pathological role mutant disease, we generated transgenic lines mice expressing human with a mutation at position 118 (hPFN1G118V). One mouse high levels PFN1 brain and spinal cord exhibited many key clinical features consistent These include loss lower (ventral horn) upper neurons (corticospinal...
Corticospinal motor neurons (CSMN) receive, integrate, and relay cerebral cortex's input toward spinal targets to initiate modulate voluntary movement. CSMN degeneration is central for numerous neuron disorders neurodegenerative diseases. Previously, 5 patients with mutations in the ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) gene were reported have neurodegeneration dysfunction upper involvement. To investigate role of UCHL1 on health stability, we used both vivo vitro approaches, took...
Mutations in the ALS2 gene result early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary suggesting prominent upper motor neuron involvement. However, importance of alsin function for corticospinal (CSMN) health stability remains unknown. To date, four separate knockout (AlsinKO) mouse models have been generated, despite hopes mimicking human pathology, none displayed profound defects. This, however, does not rule out...
Understanding mechanisms that lead to selective motor neuron degeneration requires visualization and cellular identification of vulnerable neurons. Here we report generation characterization UCHL1-eGFP hSOD1 G93A - UeGFP mice, novel reporter lines for cortical spinal Corticospinal neurons (CSMN) a subset (SMN) are genetically labeled in which express eGFP under the UCHL1 promoter. expression is stable continues through P800 vivo . Retrograde labeling, molecular marker expression,...
Transgenic mouse models expressing mutant superoxide dismutase 1 (SOD1) have been critical in furthering our understanding of amyotrophic lateral sclerosis (ALS). However, such generally overexpress the protein, which may give rise to phenotypes not directly relevant disorder. Here, we analysed a novel model that has point mutation endogenous Sod1 gene; this is identical pathological change human familial ALS (fALS) results D83G SOD1 protein. Homozgous Sod1D83G/D83G mice develop progressive...
Abstract Background The involvement of non-neuronal cells and the innate immunity has been attributed to initiation progression ALS. TDP-43 pathology is observed in a broad spectrum ALS cases one most commonly shared pathologies. potential neuroimmune axis motor cortex patients with needs be revealed. This information vital for building effective treatment strategies. Methods We investigated presence astrogliosis microgliosis pathology. prpTDP-43 A315T -UeGFP mice, corticospinal neuron...
Abstract Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected upper motor neurons (UMNs) with TDP-43 pathology, a pathology is predominantly present both familial sporadic cases amyotrophic lateral sclerosis (ALS). While same mitochondrial problems the UMNs ALS patients mouse models, since pathologies shared at cellular level, regardless species, we first analyzed metabolite profile healthy diseased cortex to investigate whether metabolomic...
Mitochondrial defects are one of the common underlying causes neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported upper motor neurons (UMNs) ALS patients with recapitulated UMNs well-characterized hTDP-43 mouse model ALS. The construct validity, shared cellular mice human, offers a unique opportunity to test treatment strategies...
Axons that carry information from the sensory periphery first elongate unbranched and form precisely ordered tracts within CNS. Later, they begin collateralizing into their proper targets terminal arbors. Target-derived factors govern axon elongation branching–arborization are not well understood. Here we report Slit2 is a major player in of central trigeminal axons brainstem. Embryonic initially develop as tract lateral brainstem; later, emit collateral branches brainstem nuclei arbors...
Recent evidence indicates the importance of innate immunity and neuroinflammation with microgliosis in amyotrophic lateral sclerosis (ALS) pathology. The MCP1 (monocyte chemoattractant protein-1) CCR2 (CC chemokine receptor 2) signaling system has been strongly associated immune responses observed ALS patients, but motor cortex not studied detail. After revealing presence to elucidate, visualize, define timing, location extent response relation upper neuron vulnerability progressive...
Abstract Background Upper motor neurons (UMNs) are a key component of neuron circuitry. Their degeneration is hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic (ALS). Currently there no preclinical assays investigating cellular responses UMNs to compound treatment, even diseases the UMNs. The basis UMN vulnerability not fully understood, has yet been identified improve health diseased UMNs: two major roadblocks building...
Neurotrophin-3 (NT-3) is required for proprioceptive neuron survival. Deletion of the proapoptotic gene Bax in NT-3 knockout mice rescues these neurons and allows examination their axon growth absence signaling. TrkC-positive peripheral central axons from dorsal root ganglia follow proper trajectories arrive close proximity to targets but fail innervate them. Peripherally, muscle spindles are absent do not enter target muscles. Centrally, branch ectopic regions spinal cord, even crossing...
Developing effective treatment strategies for neurodegenerative diseases require an understanding of the underlying cellular pathways that lead to neuronal vulnerability and progressive degeneration. To date, numerous mutations in 147 distinct genes are identified be "associated" with, "modifier" or "causative" amyotrophic lateral sclerosis (ALS). Protein products these their interactions helped determine protein landscape ALS, revealed upstream modulators, key canonical pathways,...
Mitochondrial dysfunction is one of the converging paths for many neurodegenerative diseases, including ALS (amyotrophic lateral sclerosis), and TDP-43 pathology most common proteinopathy detected in ALS/FTLD (ALS/Frontotemporal lobar degeneration). We recently identified mitochondrial problems corticospinal motor neurons (CSMN) Betz cells patients with pathology. However, timing extent defects, their mode degeneration have not been revealed. Here, we investigated health integrity...
Objective The aim of this study was to investigate the role ubiquitin C-terminal hydrolase-L1 (UCHL1) for motor neuron circuitry and especially in spinal (SMN) health, function, connectivity. Methods Since mutations UCHL1 gene leads dysfunction patients, we investigated on SMN survival, axon connectivity with muscle, by employing molecular cellular marker expression analysis electrophysiological recordings, healthy wild-type Uchl1nm3419 (UCHL1−/−) mice, which lack all function. Results There...