Future Neurology[JOURNAL]
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105 papers
The expanding genomic landscape of autism: discovering the 'forest' beyond the 'trees'.
Hu VW
Future Neurol · 2013 Jan · PMID 23637569 · Full text
Autism spectrum disorders are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. As autism spectrum disorder...
Autism spectrum disorders are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. As autism spectrum disorders are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the 'trees'). However, no single gene can account for more than 1% of the cases of autism spectrum disorders. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively transcribed and may participate in the regulation of genes, including genes on different chromosomes. This article summarizes evidence that suggests that the research spotlight needs to be expanded to encompass far-reaching gene-regulatory mechanisms that include a variety of epigenetic modifications, as well as noncoding RNA (i.e., the 'forest'). Given that noncoding RNA represents over 90% of the transcripts in most cells, we may be observing just the 'tip of the iceberg' or the 'edge of the forest' in the genomic landscape of autism.
mTOR as a potential treatment target for epilepsy.
Wong M
Future Neurol · 2012 Sep · PMID 23620711 · Full text
Current treatments for epilepsy suffer from significant limitations, including medical intractability and lack of disease-modifying or anti-epileptogenic actions. As most current seizure medications modulate ion channels...
Current treatments for epilepsy suffer from significant limitations, including medical intractability and lack of disease-modifying or anti-epileptogenic actions. As most current seizure medications modulate ion channels and neurotransmitter receptors, more effective therapies likely need to target completely different mechanisms of action. The mammalian target of rapamycin (mTOR) pathway represents a potential novel therapeutic target for epilepsy. mTOR inhibitors can suppress seizures and prevent epilepsy in animal models of certain genetic epilepsies, such as tuberous sclerosis complex. mTOR inhibitors may also be effective in some models of acquired epilepsy related to brain injury, but these effects are more variable and dependent on a number of factors. Some clinical data suggest that mTOR inhibitors decrease seizures in tuberous sclerosis complex patients, but controlled trials are lacking and no clinical data on potential anti-epileptogenic actions exist. Future basic and clinical research will help to determine the full potential of mTOR inhibitors for epilepsy.
ADVANCES IN THE CELL-BASED TREATMENT OF NEONATAL HYPOXIC-ISCHEMIC BRAIN INJURY.
Pabon MM, Borlongan CV
Future Neurol · 2013 Mar · PMID 23565051 · Full text
Stem cell therapy for adult stroke has reached limited clinical trials. Here, we provide translational research guidance on stem cell therapy for neonatal hypoxic-ischemic brain injury requiring a careful consideration o...
Stem cell therapy for adult stroke has reached limited clinical trials. Here, we provide translational research guidance on stem cell therapy for neonatal hypoxic-ischemic brain injury requiring a careful consideration of clinically relevant animal models, feasible stem cell sources, and validated safety and efficacy endpoint assays, as well as a general understanding of modes of action of this cellular therapy. To this end, we refer to existing translational guidelines, in particular the recommendations outlined in the consortium of academicians, industry partners and regulators called Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS. Although the STEPS guidelines are directed at enhancing the successful outcome of cell therapy in adult stroke, we highlight overlapping pathologies between adult stroke and neonatal hypoxic-ischemic brain injury. We are, however, cognizant that the neonatal hypoxic-ischemic brain injury displays disease symptoms distinct from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with hypoxic-ischemic brain injury.
Persistent region-dependent neuroinflammation, NMDA receptor loss and atrophy in an animal model of penetrating brain injury.
Grossman R, Paden CM, Fry PA … +2 more , Rhodes RS, Biegon A
Future Neurol · 2012 May · PMID 23539500 · Full text
UNLABELLED: Dynamic changes in neuroinflammation and glutamate NMDA receptors (NMDAR) have been noted in traumatic and ischemic brain injury. AIM: Here we investigate the time course and regional distribution of these ch...
UNLABELLED: Dynamic changes in neuroinflammation and glutamate NMDA receptors (NMDAR) have been noted in traumatic and ischemic brain injury. AIM: Here we investigate the time course and regional distribution of these changes and their relationship with atrophy in a rat model of penetrating brain injury. MATERIALS METHODS: Quantitative autoradiography, with the neuroinflammation marker [H]PK11195 and the NMDAR antagonist [I]iodoMK801, was performed on brains of animals subjected to a unilateral wireknife injury at the level of striatum and killed 3 - 60 days later. Regional atrophy was measured by morphometry. RESULTS: The injury produced large increases in [H]PK11195 binding density in cortical and septal regions adjacent to the knife track by day 7, with modest increases in the striatum. [I]iodoMK801 binding was reduced in cor tical and hippocampal regions showing marked neuroinflammation, which showed marked atrophy at subsequent time points. CONCLUSION: These results indicate that neuroinflammaton and loss of NMDAR precede and predict tissue atrophy in cortical and hippocampal regions.
Malignant synaptic growth and Alzheimer's disease.
Newman EL, Shay CF, Hasselmo ME
Future Neurol · 2012 Sep · PMID 23420180 · Full text
In this article, we will describe the malignant synaptic growth hypothesis of Alzheimer's disease. Originally presented in 1994, the hypothesis remains a viable model of the functional and biophysical mechanisms underlyi...
In this article, we will describe the malignant synaptic growth hypothesis of Alzheimer's disease. Originally presented in 1994, the hypothesis remains a viable model of the functional and biophysical mechanisms underlying the development and progression of Alzheimer's disease. In this article, we will refresh the model with references to relevant empirical support that has been generated in the intervening two decades since it's original presentation. We will include discussion of its relationship, in terms of points of alignment and points of contention, to other models of Alzheimer's disease, including the cholinergic hypothesis and the tau and β-amyloid models of Alzheimer's disease. Finally, we propose several falsifiable predictions made by the malignant synaptic growth hypothesis and describe the avenues of treatment that hold the greatest promise under this hypothesis.
Aging of the NMDA receptor: from a mouse's point of view.
Magnusson KR
Future Neurol · 2012 Sep · PMID 23316115 · Full text
Our elderly population is growing and declines in cognitive abilities, such as memory, can be costly, because it can interfere with a person's ability to live independently. The NMDA receptor is very important for many d...
Our elderly population is growing and declines in cognitive abilities, such as memory, can be costly, because it can interfere with a person's ability to live independently. The NMDA receptor is very important for many different forms of memory and this receptor is negatively affected by aging. This review examines the progress that has been made recently in characterizing selective vulnerabilities of different subunits and splice variants of the NMDA receptor to normal aging in C57BL/6 mice. Evidence is also presented for changes in the relationships of NMDA receptors to plasticity across aging. Recent interventions show that enhancing NMDA receptors in aged individuals is associated with improvements in memory, but mouse models of neurodegenerative diseases suggest that finding the right balance between too little and too much NMDA receptor activity will be the key to enhancing memory without inducing pathology.
Opening Pandora's jar: a primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders.
Khanna R, Wilson SM, Brittain JM … +4 more , Weimer J, Sultana R, Butterfield A, Hensley K
Future Neurol · 2012 Nov · PMID 23308041 · Full text
CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated funct...
CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated functions subserved by this protein. Together with its canonical roles in neurite growth and retraction and kinesin-dependent axonal transport, it is now known that CRMP2 interacts with numerous binding partners to affect microtubule dynamics; protein endocytosis and vesicular cycling, synaptic assembly, calcium channel regulation and neurotransmitter release. CRMP2 signaling is regulated by post-translational modifications, including glycosylation, oxidation, proteolysis and phosphorylation; the latter being a fulcrum of CRMP2 functions. Here, the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders are discussed and evidence is presented for therapeutic strategies targeting CRMP2 functions.
Optimizing mouse models of neurodegenerative disorders: are therapeutics in sight?
Lutz CM, Osborne MA
Future Neurol · 2013 · PMID 29479291 · Full text
The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potentia...
The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potential new therapies. Despite these advantages, mouse models of neurodegenerative disease are sometimes difficult to generate and can present challenges that must be carefully addressed when used for preclinical studies. For those models that do exist, the standardization and optimization of the models is a critical step in ensuring success in both basic research and preclinical use. This review looks back on the history of model development for neurodegenerative diseases and highlights the key strategies that have been learned in order to improve the design, development and use of mouse models in the study of neurodegenerative disease.
Alleviating brain stress: what alternative animal models have revealed about therapeutic targets for hypoxia and anoxia.
Milton SL, Dawson-Scully K
Future Neurol · 2013 · PMID 25264428 · Full text
While the mammalian brain is highly dependent on oxygen, and can withstand only a few minutes without air, there are both vertebrate and invertebrate examples of anoxia tolerance. One example is the freshwater turtle, wh...
While the mammalian brain is highly dependent on oxygen, and can withstand only a few minutes without air, there are both vertebrate and invertebrate examples of anoxia tolerance. One example is the freshwater turtle, which can withstand days without oxygen, thus providing a vertebrate model with which to examine the physiology of anoxia tolerance without the pathology seen in mammalian ischemia/reperfusion studies. Insect models such as have additional advantages, such as short lifespans, low cost and well-described genetics. These models of anoxia tolerance share two common themes that enable survival without oxygen: entrance into a state of deep hypometabolism, and the suppression of cellular injury during anoxia and upon restoration of oxygen. The study of such models of anoxia tolerance, adapted through millions of years of evolution, may thus suggest protective pathways that could serve as therapeutic targets for diseases characterized by oxygen deprivation and ischemic/reperfusion injuries.
The role of intracellular trafficking and the VPS10d receptors in Alzheimer's disease.
Reitz C
Future Neurol · 2012 Jul · PMID 23264752 · Full text
In Alzheimer's disease, the key pathological culprit is the amyloid-β protein, which is generated through β- and γ-secretase cleavage of the amyloid-β precursor protein (APP). Both the secretases and amyloid-β precursor...
In Alzheimer's disease, the key pathological culprit is the amyloid-β protein, which is generated through β- and γ-secretase cleavage of the amyloid-β precursor protein (APP). Both the secretases and amyloid-β precursor protein are transmembrane proteins that are sorted via the trans-Golgi network and the endosome through multiple membranous compartments of the cell. The coat complex clathrin controls the sorting from the cell surface and the trans-Golgi network to the endosome. Instead, the retromer controls the reverse transport from the endosome to the trans-Golgi network. The retromer contains two subprotein complexes: the cargo-selective subcomplex consisting of VPS35, VPS29 and VPS26 and the membrane deformation subcomplex consisting of Vps5p, Vps17p, SNX 1/2 and possibly SNX 5/6 or SNX 32 in mammals. Cargo molecules of the retromer include the VPS10 receptor proteins SORL1, SORT1, SORCS1, SORCS2 and SORCS3. There is increasing evidence through cell biology and animal and genetic studies that components of the retromer and the VPS10d receptor family play a role in the etiology of Alzheimer's disease. This article reviews and summarizes this current evidence.
A Critical Kinase Cascade in Neurological Disorders: PI 3-K, Akt, and mTOR.
Chong ZZ, Shang YC, Wang S … +1 more , Maiese K
Future Neurol · 2012 Nov · PMID 23144589 · Full text
Neurodegenerative disorders lead to disability and death in a significant proportion of the world's population. However, many disorders of the nervous system remain with limited effective treatments. Kinase pathways in t...
Neurodegenerative disorders lead to disability and death in a significant proportion of the world's population. However, many disorders of the nervous system remain with limited effective treatments. Kinase pathways in the nervous system that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR) offer exciting prospects for the understanding of neurodegenerative pathways and the development of new avenues of treatment. PI 3-K, Akt, and mTOR pathways are vital cellular components that determine cell fate during acute and chronic disorders, such as Huntington's disease, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and trauma. Yet, the elaborate relationship among these kinases and the variable control of apoptosis and autophagy can lead to unanticipated biological and clinical outcomes. Crucial for the successful translation of PI 3-K, Akt, and mTOR into robust and safe clinical strategies will be the further elucidation of the complex roles that these kinase pathways hold in the nervous system.
Molecular neuropathogenesis of Alzheimer's disease: an interaction model stressing the central role of oxidative stress.
Rodrigues R, Smith MA, Wang X … +4 more , Perry G, Lee HG, Zhu X, Petersen RB
Future Neurol · 2012 May · PMID 23086377 · Full text
Alzheimer's disease (AD) exhibits a complex etiology that simultaneously manifests as a complex cellular, neurobiological, molecular, anatomic-physiological and clinical entity. Other significant psychiatric conditions,...
Alzheimer's disease (AD) exhibits a complex etiology that simultaneously manifests as a complex cellular, neurobiological, molecular, anatomic-physiological and clinical entity. Other significant psychiatric conditions, such as depression and schizophrenia, may also present with complex and concurrent clinical and/or molecular phenotypes. These neuropsychiatric pathologies also originate from both environmental and genetic factors. We analyzed the molecular phenotypes of AD and discuss them with respect to the classical theories, which we integrated into mechanisms that share molecular and/or anatomical connections. Based on these mechanisms, we propose an interaction model and discuss the model in light of studies that refute or support it. Given the spectrum of AD phenotypes, we limit the scope of our discussion to a few, which facilitates concrete analysis. In addition, the study of specific, individual pathogenic phenotypes may be critical to defining the complex mechanisms leading to AD, thereby improving strategies for developing novel therapies.
Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where.
Lai AY, McLaurin J
Future Neurol · 2012 Mar · PMID 22737039 · Full text
Accumulation of senile plaques consisting of amyloid-β peptide (Aβ) aggregates is a prominent pathological feature in Alzheimer's disease. Effective clearance of Aβ from the brain parenchyma is thought to regulate the de...
Accumulation of senile plaques consisting of amyloid-β peptide (Aβ) aggregates is a prominent pathological feature in Alzheimer's disease. Effective clearance of Aβ from the brain parenchyma is thought to regulate the development and progression of the disease. Macrophages in the brain play an important role in Aβ clearance by a variety of phagocytic and digestive mechanisms. Subpopulations of macrophages are heterogeneous such that resident microglia in the parenchyma, blood macrophages infiltrating from the periphery, and perivascular macrophages residing along cerebral vessels make functionally distinct contributions to Aβ clearance. Despite phenotypic similarities between the different macrophage subsets, a series of in vivo models have been derived to differentiate their relative impacts on Aβ dynamics as well as the molecular mechanisms underlying their activities. This review discusses the key findings from these models and recent research efforts to selectively enhance macrophage clearance of Aβ.
Alzheimer's disease and epilepsy: insight from animal models.
Scharfman HE
Future Neurol · 2012 Mar · PMID 22723738 · Full text
Alzheimer's disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with e...
Alzheimer's disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy.
α-synuclein, LRRK2 and their interplay in Parkinson's disease.
Liu G, Aliaga L, Cai H
Future Neurol · 2012 Mar · PMID 22563296 · Full text
Of the various genetic factors contributing to the pathogenesis of Parkinson's disease (PD), only mutations in α-synuclein (α-syn) and LRRK2 genes cause clinical and neuropathological phenotypes closely resembling the sp...
Of the various genetic factors contributing to the pathogenesis of Parkinson's disease (PD), only mutations in α-synuclein (α-syn) and LRRK2 genes cause clinical and neuropathological phenotypes closely resembling the sporadic cases. Therefore, studying the pathophysiological functions of these two PD-related genes is particularly informative in understanding the underlying molecular pathogenic mechanism of the disease. PD-related missense and multiplication mutations in α-syn may cause both early- and late-onset PD, whereas various PD-related LRRK2 missense mutations may contribute to the more common late-onset PD. While intensive studies have been carried out to elucidate the pathogenic properties of PD-related mutant α-syn and LRRK2, our knowledge of their normal functions and their potential genetic interplay remains rudimental. In this review, we summarize the progress made regarding the pathophysiological functions of α-syn, LRRK2 and their interaction in PD, based on the available literature and our unpublished observations.
Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain.
Wu CS, Jew CP, Lu HC
Future Neurol · 2011 Jul · PMID 22229018 · Full text
Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impact...
Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized.
Evidence from the R6/2 Mouse Model of Huntington's Disease for Using Abnormal Brain Metabolism as a Biomarker for Evaluating Therapeutic Approaches for Treatment.
Parievsky A, Cepeda C, Levine MS
Future Neurol · 2012 · PMID 25892970 · Full text
Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progression of motor abnormalities as well as cognitive and psychiatric symptoms [1]. Presently, there is no cure for HD and no treat...
Huntington's disease (HD) is an autosomal dominant genetic disorder characterized by a progression of motor abnormalities as well as cognitive and psychiatric symptoms [1]. Presently, there is no cure for HD and no treatment to reverse its course or prevent its onset. HD has been characterized primarily by significant degeneration of the striatum. In addition, imaging studies have shown alterations in extra-striatal regions including the cortex [2, 3], hippocampus, and hypothalamus [4]. Although previous functional magnetic resonance imaging (fMRI) studies in patients have yielded complex and heterogeneous findings, identifying functional alterations may serve as a useful tool for tracking the progression of HD and assessing the effects of therapeutic interventions. In a recent article Cepeda-Prado et el. use novel and groundbreaking fMRI methods to elucidate functional, structural, and metabolic alterations in the R6/2 mouse model of HD. Based on changes in relative cerebral brain volume (rCBV), neuronal activity, and glucose utilization, the authors suggest that R6/2 mice have impaired neurometabolic coupling. They propose the use of rCBV as a biomarker of HD progression, providing a basis for future research examining functional alterations in animal models.
A new look at glutamate and ischemia: NMDA agonist improves long-term functional outcome in a rat model of stroke.
Dhawan J, Benveniste H, Luo Z … +3 more , Nawrocky M, Smith SD, Biegon A
Future Neurol · 2011 Nov · PMID 22140354 · Full text
Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists fa...
Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke. AIM: This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke. MATERIALS #ENTITYSTARTX00026; METHODS: Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison. RESULTS: DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy. CONCLUSION: These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.
The role of neuregulin-1 in the response to nerve injury.
Fricker FR, Bennett DL
Future Neurol · 2011 Nov · PMID 22121335 · Full text
Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types...
Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell.
Corticostriatal circuit dysfunction in Huntington's disease: intersection of glutamate, dopamine and calcium.
Miller BR, Bezprozvanny I
Future Neurol · 2010 Sep · PMID 21977007 · Full text
Huntington's disease (HD) is a noncurable and progressive autosomal-dominant neurodegenerative disorder that results from a polyglutamine expansion in the amino-terminal region of the huntingtin protein. The generation o...
Huntington's disease (HD) is a noncurable and progressive autosomal-dominant neurodegenerative disorder that results from a polyglutamine expansion in the amino-terminal region of the huntingtin protein. The generation of rodent HD models has revealed that cellular dysfunction, rather than cell death alone, occurs early in the disease progression, appearing even before overt symptom onset. Much evidence has now established that dysfunction of the corticostriatal circuit is key to HD symptomology. In this article, we summarize the most current findings that implicate glutamate, dopamine and calcium signaling in this system and discuss how they work in concert to disrupt corticostriatal function. In addition, we highlight therapeutic strategies related to altered corticostriatal signaling in HD.
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