[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence that PPARα is constitutively expressed in nuclei of hippocampal neurons and, surprisingly, controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of cyclic AMP response element binding (CREB). Accordingly, Pparα-null, but not Pparβ-null, mice are deficient in CREB and memory-associated proteins and have decreased spatial learning and memory. Small hairpin RNA knockdown of PPARα in the hippocampus suppressed CREB and NR2A, rendering wild-type animals markedly poor in consolidating spatial memory, whereas introduction of PPARα to the hippocampus of Pparα-null mice increased hippocampal CREB and NR2A and improved spatial learning and memory. Through detailed analyses of CREB and NR2A activity, as well as spatial learning and memory in bone marrow chimeric animals lacking PPARα in the CNS, we uncover a mechanism for transcriptional control of Creb and associated plasticity genes by PPARα.
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a neurodegenerative disease for which there is no cure. Therapies that are efficacious in animal models have to date shown benefit for humans. One potential powerful approach is gene therapy. The ideal method of administration of gene therapy has been hotly debated and viral vectors have provided one method of long-term and wide-spread delivery to the brain. Trophic factors to protect cells from degeneration and RNAi to reduce mutant huntingtin (mHtt) protein expression are 2 main classes of compounds that demonstrate benefit in animal models. This review will examine some commonly used adeno-associated viral (AAV) vectors and discuss some therapies that hold promise for HD.
No preview · Article · Dec 2011 · Neurobiology of Disease
[Show abstract][Hide abstract] ABSTRACT: Growth factors are potentially major players in therapeutic interventions for neurodegenerative disorders like Parkinson's disease (PD) because of their potential to not merely provide symptomatic relief but also be disease modifying agents. Many extensively utilized therapies such as the prodrug levodopa, while unquestionably effective, are intended for symptomatic benefit. Such therapies do little to stifle the progressive nature of these diseases thereby placing temporal restrictions on their effectiveness. Growth factors, by virtue of their distinct neuroprotective properties, have the cumulative effect of curbing disease progression and allaying existing symptoms. The purpose of this review is to discuss some of the growth factors commonly used in animal models of PD and those already used in clinical trials.
No preview · Article · Dec 2009 · Parkinsonism & Related Disorders
[Show abstract][Hide abstract] ABSTRACT: Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p < 0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p < 0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p < 0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V–VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p < 0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.
Full-text · Article · Apr 2009 · Neurobiology of Disease
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.
Preview · Article · Feb 2009 · Progress in brain research
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease is a genetic disorder inherited in an autosomal dominant manner. The disease is caused by a mutation manifested in the IT15 or huntingtin gene located on chromosome 4. The devastating and incurable symptoms of HD include cognitive, motor and psychiatric disturbances. The cognitive symptoms often present years before the other signs and include deficits in executive functions, procedural memory and psychomotor skills. Unfortunately no efficient therapy exists that can tackle all of these symptoms while at the same time delaying or preventing cell death. Cell death in HD occurs predominantly in the projection neurons of the striatum, and it is this population of neurons that most therapies focus on protecting. However, cortical degeneration also plays a prominent role in the manifestation of deficits in higher order cognitive functions and must be targeted while designing a therapy. The discovery of toxin-induced and genetic models in both rodents and nonhuman primates has allowed for the comprehensive testing of therapies before they reach the clinic. Pharmaceutical therapies are currently the most commonly used to treat HD patients. These may be efficient at temporarily tackling the symptoms of HD but do not address the inevitable disease progression. There are a few neuroprotective therapies currently in clinical trials, but they are somewhat limited in their effectiveness. Cell replacement strategies are also in use but have been shelved in the past few years due to lack of proper funding. This review will discuss neuroprotective gene therapies and restorative cell transplantation therapies that are in use for HD research and therapy.
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a devastating neurodegenerative disease characterized by the selective loss of neurons in the striatum and cerebral cortex. This study tested the hypothesis that an adenoassociated viral (AAV2) vector encoding for the trophic factor neurturin (NTN) could provide neuroprotection in the rat 3-nitropropionic acid (3NP) model of HD. Rats received AAV2-NTN (CERE-120), AAV2-eGFP or Vehicle, followed 4 weeks later by the mitochondrial toxin 3NP. 3NP induced motor impairments were observed on the rotarod test, the platform test, and a clinical rating scale in all groups. However, each of these deficits was attenuated by AAV2-NTN (CERE-120). Stereological counts revealed a significant protection of NeuN-ir striatal neurons from 3NP toxicity by AAV2-NTN. These data support the concept that AAV2-NTN might be a valuable treatment for patients with Huntington's disease.
Full-text · Article · Jun 2007 · Neurobiology of Disease
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a neurological disorder caused by a genetic mutation in the IT15 gene. Progressive cell death
in the striatum and cortex, and accompanying declines in cognitive, motor, and psychiatric functions, are characteristic of
the disease. Animal models of HD have provided insight into disease pathology and the outcomes of therapeutic strategies.
Earlier studies of HD most often used toxin-induced models to study mitochondrial impairment and excitotoxicity-induced cell
death, which are both mechanisms of degeneration seen in the HD brain. These models, based on 3-nitropropionic acid and quinolinic
acid, respectively, are still often used in HD studies. The discovery in 1993 of the huntingtin mutation led to the creation
of newer models that incorporate a similar genetic defect. These models, which include transgenic and knock-in rodents, are
more representative of the HD progression and pathology. An even more recent model that uses a viral vector to encode the
gene mutation in specific areas of the brain may be useful in nonhuman primates, as it is difficult to produce genetic models
in these species. This article examines the aforementioned models and describes their use in HD research, including aspects
of the creation, delivery, pathology, and tested therapies for each model.
Full-text · Article · Feb 2007 · ILAR journal / National Research Council, Institute of Laboratory Animal Resources
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a devastating neurodegenerative disorder that occurs in patients with a mutation in the huntingtin or IT15 gene. Patients are plagued by early cognitive signs, motor deficits, and psychiatric disturbances. Symptoms are attributed to cell death in the striatum and disruption of cortical-striatal circuitry. Mechanisms of cell death are unclear, but processes involving mitochondrial abnormalities, excitotoxicity, and abnormal protein degradation have been implicated. Many factors likely contribute to neuron death and dysfunction, and this has made it difficult to systematically address the pathology in HD. Pharmaceutical therapies are commonly used in patients to treat disease symptoms. These have limited benefit and do not address the inexorable disease progression. Several neuroprotective therapies are being evaluated in animal models of HD as well as in clinical trials. Similarly, cell replacement strategies such as fetal transplantation have been used in the clinic with minimal success, making future cell replacement strategies such as stem cell therapy uncertain. This review describes the disease pathology in HD and addresses many of the past and emerging therapeutic strategies.
Full-text · Article · Feb 2007 · Cell Transplantation
[Show abstract][Hide abstract] ABSTRACT: Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.
Full-text · Article · Jul 2006 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: Neurogenesis following neural degeneration has been demonstrated in many models of disease and injury. The present study further examines the early proliferative and migratory response of the brain to a controlled cortical impact (CCI) model of traumatic brain injury. The CCI was centered over the forelimb sensorimotor cortex, unilaterally, in the adult mouse. To examine proliferation, bromo-deoxyuridine (BrdU) was injected i.p. immediately post-injury and on post-injury days 1, 2, and 3. To assess migration, we labeled SVZ cells with inert latex microspheres immediately post-injury. By combining microsphere labeling with BrdU, we determined if migrating cells had gone through the S-phase of the cell cycle after the lesion. In addition, we used a marker of neurogenesis and migration, doublecortin, to further characterize the response of the SVZ to the injury. Lastly, we determined whether subregions of the SVZ respond differentially to injury. The current study demonstrates that 3 days following CCI cellular proliferation is seen around the cortex, in the SVZ, corpus callosum, and subcortical areas anatomically connected to, but not directly damaged by the impact. It delineates that an increase in proliferation occurs in the dorsal-most aspect of the ipsilateral SVZ following impact. Lastly, it demonstrates that proliferating cells migrate from the SVZ to cortical and subcortical structures affected by the injury and that some of these cells are migrating neuroblasts.