Article
Neurosciences
Julien Chambon, Pragya Komal, Gil M. Lewitus, Gina M. Kemp, Simone Valade, Houaria Adaidi, Noura Al Bistami, David Stellwagen
Summary: Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin gene. Neurodegeneration in HD first occurs in the striatum, accompanied by an elevation in inflammatory cytokines. In a mouse model of HD, early changes in synaptic input onto striatal medium spiny neurons were observed, including an increase in excitatory synaptic strength and a decrease in inhibitory synaptic strength, which are both dependent on the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) signaling. These changes may contribute to the development of excitotoxicity during the progress of HD.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Multidisciplinary Sciences
Foteini Paraskevopoulou, Poorya Parvizi, Gokce Senger, Nurcan Tuncbag, Christian Rosenmund, Ferah Yildirim
Summary: Transcriptional dysregulation in Huntington's disease (HD) leads to functional deficits in striatal neurons. Mutant Huntingtin (Htt) decreases synaptic output of striatal neurons autonomously, with a number of dysregulated genes linked to physiological deficiencies in mutant Htt neurons. Inhibiting histone deacetylase 1/3 activities rectifies functional and morphological deficits, as well as alleviates aberrant transcriptional profiles in mutant Htt neurons.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Neurosciences
Melissa Serranilla, Melanie A. Woodin
Summary: The regulation of intracellular chloride levels is crucial for maintaining fast synaptic inhibition, which is primarily mediated by the cation-chloride cotransporters NKCC1 and KCC2. In healthy neurons, the expression of KCC2 is higher than NKCC1, resulting in lower levels of intracellular chloride. However, in immature neurons or neurological disorders, impaired KCC2 function and/or enhanced NKCC1 expression lead to chloride accumulation and GABA-mediated excitation. This review focuses on the role of chloride dysregulation in the healthy and Huntington's disease brain, with a particular emphasis on the basal ganglia circuitry and the potential therapeutic targets.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Clinical Neurology
Ellen T. Koch, Marja D. Sepers, Judy Cheng, Lynn A. Raymond
Summary: This study investigated the correlation between striatal activity and behavior in a Huntington's disease mouse model. Decreased striatal activity was observed during motor learning, with an inverse correlation between latency to fall and striatal activity. At an early stage, the YAC128 mice did not show a deficit in latency to fall but exhibited significant differences in paw kinematics and a weaker correlation between latency to fall and striatal activity. However, at 6 to 7 months, the YAC128 mice showed reduced latency to fall, impaired paw kinematics, and increased striatal activity. In the open field, elevated neuronal activity was observed at rest in the YAC128 mice.
MOVEMENT DISORDERS
(2022)
Article
Neurosciences
Karim S. Ibrahim, Salah El Mestikawy, Khaled S. Abd-Elrahman, Stephen S. G. Ferguson
Summary: Huntington's disease (HD) is a neurodegenerative disease characterized by motor and cognitive impairments. The role of vesicular glutamate transporter-3 (VGLUT3) in HD pathophysiology is unclear. This study found that VGLUT3 deletion rescued motor and cognitive deficits in HD mouse models, likely through the activation of Akt and ERK1/2 pathways. These findings suggest that VGLUT3 could be a potential target for HD therapeutics.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Cristine De Paula Nascimento-Castro, Elisa C. Winkelmann-Duarte, Gianni Mancini, Priscilla Gomes Welter, Evelini Placido, Marcelo Farina, Joana Gil-Mohapel, Ana Lucia S. Rodrigues, Andreza Fabro de Bem, Patricia S. Brocardo
Summary: Huntington's disease is a genetic neurodegenerative disease that affects motor, psychiatric, and cognitive functions. Recent evidence suggests that the emotional and cognitive deficits observed in patients with HD might be associated with hippocampal dysfunction. In this study using a HD mouse model, researchers found that mice in the late symptomatic stage exhibited depressive-like behavior and cognitive deficits. Additionally, they observed degenerative changes in the hippocampal dentate gyrus, including the presence of dark neurons and structural alterations in the rough endoplasmic reticulum and Golgi apparatus.
Article
Neurosciences
Johannes Burtscher, Giuseppe Pepe, Federico Marracino, Luca Capocci, Susy Giova, Gregoire P. Millet, Alba Di Pardo, Vittorio Maglione
Summary: Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized by defects in mitochondrial homeostasis and functions, including age-related changes in respiratory capacities. The study found differential expression of ETS components in the cortex and striatum of symptomatic R6/2 mice, indicating transcription, translation and/or mitochondrial import defects in R6/2 mouse brains.
Review
Clinical Neurology
Carlos Cepeda, Michael S. Levine
Summary: The understanding of the changes in cerebral cortex and basal ganglia in Huntington's disease has greatly improved with the help of genetic animal models. Recent studies have shown that synaptic dysfunction in the cortico-basal ganglia-cortical loop is influenced by cortical maldevelopment and disconnection in the corticostriatal pathway. Additionally, biphasic changes in glutamate and dopamine release in the striatum may explain the different symptoms in early and late stages of the disease.
Review
Multidisciplinary Sciences
Baljit S. Khakh, Steven A. Goldman
Summary: Huntington's disease (HD) is a fatal neurodegenerative disease caused by a mutation in the huntingtin gene. Astrocytes in the striatum, a brain region affected in HD, play a role in the pathology of the disease. Dysfunctions in astrocytes contribute to cellular and metabolic abnormalities in HD, suggesting the potential for therapeutic targeting of these cells to restore normal function.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2023)
Article
Neurosciences
Iris Alvarez-Merz, Javier G. Luengo, Maria-Dolores Munoz, Jesus M. Hernandez-Guijo, Jose M. Solis
Summary: The study demonstrates that the application of an amino acid mixture at physiological concentrations can lead to cell swelling and affect synaptic function. Specifically, the amino acids in Plasma1 accumulate intracellularly and induce synaptic potentiation.
Review
Neurosciences
Guendalina Bergonzoni, Jessica Doring, Marta Biagioli
Summary: Huntington's disease is a devastating neurodegenerative disorder caused by an aberrant expansion of the CAG tract within the HTT gene. Despite the ubiquity of the HTT gene, striatal Medium-sized Spiny Neurons are particularly vulnerable to the HD mutation, with D1R and D2R displaying different susceptibility. Understanding cell type-specific gene expression dysregulation in the striatum may offer new paths for therapeutic intervention in HD patients.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Review
Neurosciences
Seung Jae Hyeon, Jinyoung Park, Junsang Yoo, Su-Hyun Kim, Yu Jin Hwang, Seung-Chan Kim, Tian Liu, Hyun Soo Shim, Yunha Kim, Yakdol Cho, Jiwan Woo, Key-Sun Kim, Richard H. Myers, Hannah L. Ryu, Neil W. Kowall, Eun Joo Song, Eun Mi Hwang, Hyemyung Seo, Junghee Lee, Hoon Ryu
Summary: Mitochondrial dysfunction in Huntington's disease is associated with a decrease in XIAP-p53 colocalization and a reduction in XIAP levels due to mutant Huntingtin overexpression, leading to mitochondrial localization of p53. XIAP interacts with p53 C-terminal domain and decreases its stability via autophagy, preventing mitochondrial oxidative stress and cell death. Dysregulation of XIAP triggers mitochondrial dysfunction and neuropathological processes, while XIAP overexpression improves neuropathology in mouse models of HD.
PROGRESS IN NEUROBIOLOGY
(2021)
Article
Clinical Neurology
Iris Alvarez-merz, Maria-dolores Munoz, Jesus M. Hernandez-guijo, Jose M. Solis
Summary: Non-excitatory amino acids (AA) can induce membrane depolarization and affect synaptic transmission during hypoxia. The mixture of L-alanine, glycine, L-glutamine, and L-serine can reliably provoke this effect. AA transporters, such as system N and alanine-serine-cysteine transporter 2 (ASCT2), may serve as therapeutic targets for brain ischemia treatment.
TRANSLATIONAL STROKE RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Xiong Yang, Shi-feng Chu, Zhen-zhen Wang, Fang-fang Li, Yu-he Yuan, Nai-hong Chen
Summary: Ginsenoside Rg1 shows potential neuroprotective effects in a mouse model of Huntington's disease, alleviating weight loss, behavioral defects, and neuronal loss, possibly through inhibiting the activation of MAPKs and NF-kappa Beta signaling pathways. It may serve as a novel therapeutic option for Huntington's disease.
ACTA PHARMACOLOGICA SINICA
(2021)
Article
Clinical Neurology
Jannis Achenbach, Simon Faissner, Carsten Saft
Summary: This study investigated the effects of the phosphodiesterase-5 inhibitor sildenafil in Huntington's Disease patients, and found beneficial effects on motor, functional, and cognitive capacities. These effects were not explained by genetic or demographic factors. It remains unclear whether these effects are due to behavioral differences or direct neurobiological modulations caused by the drug.
JOURNAL OF NEUROLOGY
(2022)
Review
Neurosciences
Sandra M. Holley, Talia Kamdjou, Jack C. Reidling, Brian Fury, Dane Coleal-Bergum, Gerhard Bauer, Leslie M. Thompson, Michael S. Levine, Carlos Cepeda
CNS NEUROSCIENCE & THERAPEUTICS
(2018)
Article
Neurosciences
Sandra M. Holley, Laurie Galvan, Talia Kamdjou, Carlos Cepeda, Michael S. Levine
EUROPEAN JOURNAL OF NEUROSCIENCE
(2019)
Article
Engineering, Biomedical
Stephanie K. Seidlits, Jesse Liang, Rebecca D. Bierman, Alireza Sohrabi, Joshua Karam, Sandra M. Holley, Carlos Cepeda, Christopher M. Walthers
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
(2019)
Article
Medicine, General & Internal
Evelyn Medawar, Tiffanie A. Benway, Wenfei Liu, Taylor A. Hanan, Peter Haslehurst, Owain T. James, Kenrick Yap, Laurenz Muessig, Fabia Moroni, Muzammil A. Nahaboo Solim, Gaukhar Baidildinova, Rui Wang, Jill C. Richardson, Francesca Cacucci, Dervis A. Salih, Damian M. Cummings, Frances A. Edwards
Review
Neurosciences
Carlos Cepeda, Katerina D. Oikonomou, Damian Cummings, Joshua Barry, Vannah-Wila Yazon, Dickson T. Chen, Janelle Asai, Christopher K. Williams, Harry V. Vinters
JOURNAL OF NEUROSCIENCE RESEARCH
(2019)
Review
Neurosciences
Karina S. Vitanova, Katie M. Stringer, Diana P. Benitez, Jonathan Brenton, Damian M. Cummings
JOURNAL OF NEUROSCIENCE RESEARCH
(2019)
Article
Cell Biology
Kwang Lee, Konstantin Bakhurin, Leslie D. Claar, Sandra M. Holley, Natalie C. Chong, Carlos Cepeda, Michael S. Levine, Sotiris C. Masmanidis
Article
Biochemistry & Molecular Biology
Wenfei Liu, Orjona Taso, Rui Wang, Sevinc Bayram, Andrew C. Graham, Pablo Garcia-Reitboeck, Anna Mallach, William D. Andrews, Thomas M. Piers, Juan A. Botia, Jennifer M. Pocock, Damian M. Cummings, John Hardy, Frances A. Edwards, Dervis A. Salih
HUMAN MOLECULAR GENETICS
(2020)
Article
Neurosciences
Diana P. Benitez, Shenyi Jiang, Jack Wood, Rui Wang, Chloe M. Hall, Carlijn Peerboom, Natalie Wong, Katie M. Stringer, Karina S. Vitanova, Victoria C. Smith, Dhaval Joshi, Takashi Saito, Takaomi C. Saido, John Hardy, Jorg Hanrieder, Bart De Strooper, Dervis A. Salih, Takshashila Tripathi, Frances A. Edwards, Damian M. Cummings
Summary: The study found that microglial response to increased amyloid beta levels is delayed, with an increase in glutamate release probability observed in knock-in and transgenic mouse models of Alzheimer's disease. The findings suggest that alterations in surviving phagocytic microglia, rather than microglial loss, may play a role in age-dependent effects on glutamate release, which become exacerbated in Alzheimer's disease.
MOLECULAR NEURODEGENERATION
(2021)
Article
Biology
Ana C. Sias, Ashleigh K. Morse, Sherry Wang, Venuz Y. Greenfield, Caitlin M. Goodpaster, Tyler M. Wrenn, Andrew M. Wikenheiser, Sandra M. Holley, Carlos Cepeda, Michael S. Levine, Kate M. Wassum
Summary: The study found that the basolateral amygdala (BLA) is crucial for encoding sensory-specific stimulus-outcome memories during the learning process and influencing reward choices. Direct input from the lateral orbitofrontal cortex (lOFC) supports the BLA in this function, and the pathways between them regulate the encoding and subsequent use of sensory-specific reward memories that are essential for adaptive, appetitive decision making.
Article
Neurosciences
S. M. Holley, K. D. Oikonomou, C. M. Swift, L. Mohan, B. Matthews, O. Vega, G. Mkrtchyan, C. Cepeda, M. S. Levine
Summary: As Huntington's disease progresses, there is a loss of neurons in the striatum and thinning of the cerebral cortex. This study found reduced connectivity between thalamic cells and their targeted cortical regions in a mouse model of HD, suggesting impaired thalamocortical information transmission.
Article
Materials Science, Multidisciplinary
Amelia V. Edwards, Christopher Hann, Henry Ivill, Hanna Leeson, Larysa Tymczyszyn, Damian M. Cummings, Mark D. Ashton, Garry R. Harper, Diane T. Spencer, Wan Li Low, Kiron Rajeev, Pierre Martin-Hirsch, Frances A. Edwards, John G. Hardy, Allan E. W. Rennie, David Cheneler
Summary: This study demonstrates the use of additive manufacturing to prepare inexpensive multielectrode arrays and their ability to interact with ex vivo brain tissue.
MATERIALS ADVANCES
(2021)
Article
Clinical Neurology
Dervis A. Salih, Sevinc Bayram, Sebastian Guelfi, Regina H. Reynolds, Maryam Shoai, Mina Ryten, Jonathan W. Brenton, David Zhang, Mar Matarin, Juan A. Botia, Runil Shah, Keeley J. Brookes, Tamar Guetta-Baranes, Kevin Morgan, Eftychia Bellou, Damian M. Cummings, Valentina Escott-Price, John Hardy
BRAIN COMMUNICATIONS
(2019)
Article
Neurosciences
Sandra M. Holley, Laurie Galvan, Talia Kamdjou, Ashley Dong, Michael S. Levine, Carlos Cepeda
FRONTIERS IN SYNAPTIC NEUROSCIENCE
(2019)
Meeting Abstract
Clinical Neurology
J. C. Reidling, S. M. Holley, C. Cepeda, A. Relano-Gines, J. Ochaba, C. Moore, B. Fury, A. Lau, S. Yeung, J. S. Steffan, M. Blurton-Jones, C. K. Meshul, G. Bauer, M. F. Chesselet, M. S. Levine, C. N. Svendsen, L. M. Thompson