Neuroscience
Abstract
Creatine transporter (CrT) upholds the brain creatine (Cr) levels, but the impacts of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments of CrT-deficiency, the second most common cause of X-linked intellectual disabilities. Herein we examined the consequences of CrT-deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplement. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained the baseline brain ATP level with a tendency towards the pAMPK/autophagy from mTOR signaling activity. Starvation elevated the signaling imbalance and reduced the brain ATP level in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy/mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/NAA (N-acetylaspartate) ratio, partially averted the signaling imbalance, and reduced the infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions of CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplement may be an effective treatment of congenital CrT-deficiency and acute brain injury.
Authors
Hong-Ru Chen, Xiaohui Zhang-Brotzge, Yury M. Morozov, Yuancheng Li, Siming Wang, Helen Zhang, Irena S. Kuan, Elizabeth M. Fugate, Hui Mao, Yu-Yo Sun, Pasko Rakic, Diana M. Lindquist, Ton DeGrauw, Chia-Yi Kuan
Abstract
Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.
Authors
Danique Beijer, Hong Joo Kim, Lin Guo, Kevin O’Donovan, Inès Mademan, Tine Deconinck, Kristof Van Schil, Charlotte M. Fare, Lauren E. Drake, Alice F. Ford, Andrzej Kochański, Dagmara Kabzińska, Nicolas Dubuisson, Peter Van den Bergh, Nicol C. Voermans, Richard J.L.F. Lemmers, Silvère M. van der Maarel, Devon Bonner, Jacinda B. Sampson, Matthew T. Wheeler, Anahit Mehrabyan, Steven Palmer, Peter De Jonghe, James Shorter, J. Paul Taylor, Jonathan Baets
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify potentially novel treatments to alleviate muscle pathology combining transcriptomics, proteomics, and perturbational data sets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including lifespan, weight, and key molecular networks in skeletal muscle. Our work highlights the potential of multiple and parallel data-driven approaches for the development of potentially novel treatments for use in combination with SMN restoration therapies.
Authors
Katharina E. Meijboom, Viola Volpato, Jimena Monzón-Sandoval, Joseph M. Hoolachan, Suzan M. Hammond, Frank Abendroth, Olivier G. de Jong, Gareth Hazell, Nina Ahlskog, Matthew J.A. Wood, Caleb Webber, Melissa Bowerman
Abstract
Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in AD physiopathology impairs lipid synthesis needed for cortical networks activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation are inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by PPARα specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process.
Authors
Francisco Sáez-Orellana, Thomas Leroy, Floriane Ribeiro, Anna Kreis, Karelle Leroy, Fanny Lalloyer, Eric Baugé, Bart Staels, Charles Duyckaerts, Jean-Pierre Brion, Philippe Gailly, Jean-Noël Octave, Nathalie Pierrot
Abstract
The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as postnatal day 10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganised microtubule networks and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in post-mortem cortices of human MPS patients suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients.
Authors
Camila Pará, Poulomee Bose, Luigi Bruno, Erika Freemantle, Mahsa Taherzadeh, Xuefang Pan, Chanshuai Han, Peter S. McPherson, Jean-Claude Lacaille, Éric Bonneil, Pierre Thibault, Claire O'Leary, Brian Bigger, Carlos Ramon Morales, Graziella Di Cristo, Alexey V. Pshezhetsky
Abstract
SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel’s distal intracellular C-terminal domain and analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in wild type and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.
Authors
Hong-Gang Wang, Charlotte C. Bavley, Anfei Li, Rebecca M. Jones, Jonathan E. Hackett, Yared Bayleyen, Francis S. Lee, Anjali M. Rajadhyaksha, Geoffrey S. Pitt
Abstract
Neurogenic muscle atrophy is the loss of skeletal muscle mass and function that occurs with nerve injury and in denervating diseases such as amyotrophic lateral sclerosis. Aside from prompt restoration of innervation and exercise where feasible, there are currently no effective strategies for maintaining skeletal muscle mass in the setting of denervation. We conducted a longitudinal analysis of gene expression changes occurring in atrophying skeletal muscle, and identified Gadd45a as a gene that shows one of the earliest and most sustained increases in expression in skeletal muscle after denervation. We evaluated the role of this induction using genetic mouse models and found that mice lacking GADD45A show accelerated and exacerbated neurogenic muscle atrophy, as well as loss of fiber type identity. Our genetic analyses demonstrate that, rather than directly contributing to muscle atrophy as proposed in earlier studies, GADD45A induction likely represents a protective negative feedback response to denervation. Establishing the downstream effectors that mediate this protective effect and the pathways they participate in may yield new opportunities to modify the course of muscle atrophy.
Authors
Jeffrey T. Ehmsen, Riki Kawaguchi, Damlanur Kaval, Anna E. Johnson, Daniel Nachun, Giovanni Coppola, Ahmet Höke
Abstract
Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1GFP/+–knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified — growth arrest–specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) — might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury.
Authors
Andrés Cruz-Herranz, Frederike C. Oertel, Kicheol Kim, Ester Cantó, Garrett Timmons, Jung H. Sin, Michael Devereux, Nicholas Baker, Brady Michel, Ryan D. Schubert, Lakshmisahithi Rani, Christian Cordano, Sergio E. Baranzini, Ari J. Green
Abstract
Individuals with heart failure (HF) frequently present with comorbidities, including obesity, insulin resistance, hypertension, and dyslipidemia. Many patients with HF experience cardiogenic dementia, yet the pathophysiology of this disease remains poorly understood. Using a swine model of cardiometabolic HF (Western diet+aortic banding; WD-AB), we tested the hypothesis that WD-AB would promote a multidementia phenotype involving cerebrovascular dysfunction alongside evidence of Alzheimer’s disease (AD) pathology. The results provide evidence of cerebrovascular insufficiency coupled with neuroinflammation and amyloidosis in swine with experimental cardiometabolic HF. Although cardiac ejection fraction was normal, indices of arterial compliance and cerebral blood flow were reduced, and cerebrovascular regulation was impaired in the WD-AB group. Cerebrovascular dysfunction occurred concomitantly with increased MAPK signaling and amyloidogenic processing (i.e., increased APP, BACE1, CTF, and Aβ40 in the prefrontal cortex and hippocampus) in the WD-AB group. Transcriptomic profiles of the stellate ganglia revealed the WD-AB group displayed an enrichment of gene networks associated with MAPK/ERK signaling, AD, frontotemporal dementia, and a number of behavioral phenotypes implicated in cognitive impairment. These provide potentially novel evidence from a swine model that cerebrovascular and neuronal pathologies likely both contribute to the dementia profile in a setting of cardiometabolic HF.
Authors
Bradley J. Baranowski, Matti D. Allen, Jennifer N.K. Nyarko, R. Scott Rector, Jaume Padilla, Darrell D. Mousseau, Christoph D. Rau, Yibin Wang, M. Harold Laughlin, Craig A. Emter, Rebecca E.K. MacPherson, T. Dylan Olver
Natural killer cells associate with amyotrophic lateral sclersois in a sex- and age-dependent manner
Abstract
NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. In mice, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively collected blood from ALS and control subjects; longitudinal changes in these metrics were correlated to Revised ALS Functional Rating Scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers were elevated in ALS subjects, and changes in CXCR3+ NK cells and seven trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age impacted the associations between ALSFRS-R and markers NKG2D and NKp46, while sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.
Authors
Benjamin J. Murdock, Joshua P. Famie, Caroline E. Piecuch, Kristen D. Raue, Faye E. Mendelson, Cole H. Pieroni, Sebastian D. Iniguez, Lili Zhao, Stephen A. Goutman, Eva L. Feldman
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