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ELECTROCONVULSIVE SHOCK AMELIORATES DISEASE PROCESSES AND EXTENDS SURVIVAL IN HUNTINGTON MUTANT MICE
Title
ELECTROCONVULSIVE SHOCK AMELIORATES DISEASE PROCESSES AND EXTENDS SURVIVAL IN HUNTINGTON MUTANT MICE.
Creator
Baharani, Akanksha, Chan, Sic L., University of Central Florida
Abstract / Description
ABSTRACT Huntington's disease (HD) is a devastating autosomal dominantly inherited neurological disorder caused by an abnormal expansion of CAG trinucleotide repeats in the gene coding for the N-terminal region of the huntingtin (Htt) protein, which leads to the formation of a polyglutamine stretch. The greater the CAG repeats, the earlier the onset of the disease. The polyglutamine stretch destabilizes the Htt protein leading to misfolding, abnormal processing, aggregation, and inclusion...
Show moreABSTRACT Huntington's disease (HD) is a devastating autosomal dominantly inherited neurological disorder caused by an abnormal expansion of CAG trinucleotide repeats in the gene coding for the N-terminal region of the huntingtin (Htt) protein, which leads to the formation of a polyglutamine stretch. The greater the CAG repeats, the earlier the onset of the disease. The polyglutamine stretch destabilizes the Htt protein leading to misfolding, abnormal processing, aggregation, and inclusion formation. Mutant Htt protein is believed to damage and kill neurons in the striatum by a mechanism involving increased oxidative and metabolic stress, and impaired adaptive cellular stress responses. A large number of abnormalities have been reported in HD, including transcription deficits, energy impairment, excitotoxicity, and lack of trophic support. Reduced trophic support contributes importantly to striatal degeneration in human HD. Specifically, brain-derived neurotrophic factor (BDNF) expression is reduced in patients with HD. BDNF is also decreased in brain tissue from mice transgenic for mutant Htt. BDNF levels influences the onset and the severity of motor dysfunction in HD mice. In addition to BDNF, levels of the molecular chaperones heat shock proteins (Hsp40 and 70) decrease progressively in HD brain. Hsp70 is a highly stress-inducible member of a chaperone family of proteins that functions to prevent misfolding and aggregation of newly synthesized mutant proteins and stress-denatured proteins. Hsps appear to play a critical role in HD since expression of active heat shock factor HSF1, a transcription factor responsible for the induction of Hsps, markedly reduces polyglutamine aggregate formation in both cell and mouse models. Many efforts have been made to develop preventive treatments for HD because of the strong genetic link and a freely available genetic test to identify individuals at risk. At present, only symptomatic therapy is available and effective therapeutic approaches to slow the disease process have yet to be developed. Previous studies have shown that electroconvulsive shock (ECS) induces the production of growth factors including BDNF and the molecular chaperones HSP40 and HSP70. Because ECS can stimulate the production of neuroprotective proteins, we determined whether ECS treatment could slow the progressive nature of the disease process and provide a therapeutic benefit in a mouse model of HD. ECS or sham treatment was administered to male N171-82Q Htt mutant mice. End points measured included motor function, striatal and cortical pathology, and levels of neurotrophic factors, protein chaperones, and proteins involved in synaptic plasticity. ECS treatment delayed the onset of motor symptoms, reduced body weight loss and extended the survival of HD mice. Striatal neurodegeneration was attenuated and levels of neurotrophic factors, protein chaperones and mitochondria-stabilizing protein were elevated in striatal cells of ECS-treated compared to sham-treated HD mice. Our findings suggest that ECS can increase the resistance of neurons to mutant huntingtin resulting in improved functional outcome and extended survival. The potential of ECS as a treatment for HD patients merits further consideration.
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Date Issued
2010
Identifier
CFE0003486, ucf:48981
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0003486
INVESTIGATING THE ROLE OF THE GUT MICROBIOME IN HUNTINGTON DISEASE
Title
INVESTIGATING THE ROLE OF THE GUT MICROBIOME IN HUNTINGTON DISEASE.
Creator
Hart, Casey G, Southwell, Amber, University of Central Florida
Abstract / Description
Huntington disease (HD) is an inherited neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Metabolic dysfunction is a feature of HD that is recapitulated in HD mouse models. Our lab has shown that circadian feeding rhythms are disrupted in humanized HD mice and restored by suppression of brain HTT. Furthermore, when circadian feeding rhythm is artificially restored, in addition to normalization of metabolic function, liver and striatal HTT is...
Show moreHuntington disease (HD) is an inherited neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Metabolic dysfunction is a feature of HD that is recapitulated in HD mouse models. Our lab has shown that circadian feeding rhythms are disrupted in humanized HD mice and restored by suppression of brain HTT. Furthermore, when circadian feeding rhythm is artificially restored, in addition to normalization of metabolic function, liver and striatal HTT is temporarily reduced, demonstrating that HTT is involved in gut-brain feedback. The gut microbiome, which can regulate gut-brain feedback, has been implicated in the pathogenesis of other central nervous system disorders and we hypothesize it also plays a role in HD. The objective of this study is to investigate alterations in relative abundance of HD gut microbiota using existing plasma metabolomics data to identify candidate bacteria. If distinct microbiota profiles are demonstrated, this would provide the basis for future unbiased studies to investigate the complete HD microbiome.
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Date Issued
2018
Identifier
CFH2000418, ucf:45814
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000418
Defective Dynamics of Mitochondria in Amyotrophic Lateral Sclerosis and Huntington's Disease
Title
Defective Dynamics of Mitochondria in Amyotrophic Lateral Sclerosis and Huntington's Disease.
Creator
Song, Wenjun, Bossy-Wetzel, Ella, Fernandez-Valle, Cristina, Cheng, Zixi, Self, William, University of Central Florida
Abstract / Description
Mitochondria play important roles in neuronal function and survival, including ATP production, Ca2+ buffering, and apoptosis. Mitochondrial dysfunction is a common event in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD); however, what causes the mitochondrial dysfunction remains unclear. Mitochondrial fission is mediated by dynamin-related protein 1 (DRP1) and fusion by mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1),...
Show moreMitochondria play important roles in neuronal function and survival, including ATP production, Ca2+ buffering, and apoptosis. Mitochondrial dysfunction is a common event in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD); however, what causes the mitochondrial dysfunction remains unclear. Mitochondrial fission is mediated by dynamin-related protein 1 (DRP1) and fusion by mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1), which are essential for mitochondrial function. Mutations in the mitochondrial fission and fusion machinery lead to neurodegeneration. Thus, whether defective mitochondrial dynamics participates in ALS and HD requires further investigation.ALS is a fatal neurodegenerative disease characterized by upper and lower motor neuron loss. Mutations in Cu/Zn superoxide dismutase (SOD1) cause the most common familiar form of ALS by mechanisms not fully understood. Here, a new motor neuron-astrocyte co-culture system was created and live-cell imaging was used to evaluate mitochondrial dynamics. Excessive mitochondrial fission was observed in mutant SOD1G93A motor neurons, correlating with impaired axonal transport and neuronal cell death. Inhibition of mitochondrial fission restored mitochondrial dynamics and protected neurons against SOD1G93A-induced mitochondrial fragmentation and neuronal cell death, implicating defects in mitochondrial dynamics in ALS pathogenesis.HD is an inherited neurodegenerative disorder caused by glutamine (Q) expansion in the polyQ region of the huntingtin (HTT) protein. In the current work, mutant HTT caused mitochondrial fragmentation in a polyQ-dependent manner in both primary cortical neurons and fibroblasts from human patients. An abnormal interaction between DRP1 and HTT was observed in mutant HTT mice and inhibition of mitochondrial fission or promotion of mitochondrial fusion restored mitochondrial dynamics and protected neurons against mutant HTT-induced cell death. Thus, mutant HTT may increase mitochondrial fission by elevating DRP1 GTPase activity, suggesting that mitochondrial dynamics plays a causal role in HD.In summary, rebalanced mitochondrial fission and fusion rescues neuronal cell death in ALS and HD, suggesting that mitochondrial dynamics could be the molecular mechanism underlying these diseases. Furthermore, DRP1 might be a therapeutic target to delay or prevent neurodegeneration.
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Date Issued
2012
Identifier
CFE0004444, ucf:49356
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0004444
INVESTIGATING THE ROLE OF THE CASPASE-6 CLEAVAGE FRAGMENT OF MUTANT HUNTINGTIN IN HUNTINGTON DISEASE PATHOGENESIS
Title
INVESTIGATING THE ROLE OF THE CASPASE-6 CLEAVAGE FRAGMENT OF MUTANT HUNTINGTIN IN HUNTINGTON DISEASE PATHOGENESIS.
Creator
McKinnis, Jourdan A, Southwell, Amber, University of Central Florida
Abstract / Description
Huntington disease (HD) is a devastating and fatal neurodegenerative disease. At the moment, no disease modifying therapies are available, with only symptomatic treatment offered to alleviate psychiatric and some types of motor deficits. As a result, many people will continue to suffer and die from this disease. Small molecule therapies have failed to provide benefit in HD, necessitating more complex gene therapy approaches and the identification of less traditional therapeutic targets. A...
Show moreHuntington disease (HD) is a devastating and fatal neurodegenerative disease. At the moment, no disease modifying therapies are available, with only symptomatic treatment offered to alleviate psychiatric and some types of motor deficits. As a result, many people will continue to suffer and die from this disease. Small molecule therapies have failed to provide benefit in HD, necessitating more complex gene therapy approaches and the identification of less traditional therapeutic targets. A previous study demonstrated that preventing cleavage of the huntingtin (HTT) protein, the protein that when mutated causes HD, by caspase 6 (C6) at amino acid 586 prevents the onset of disease in transgenic HD model mice. This suggests that inhibiting the toxicity initiated by N586 cleavage could be a promising therapeutic strategy, but a safe and specific way to do this in humans has not been identified. General C6 inhibition is not a feasible strategy due to the vital functions it plays throughout life. Thus, the purpose of this study was to investigate whether the C6 cleavage fragment of HTT, N586, is itself a toxic species of HTT or if it initiates a toxic proteolytic pathway in order to identify more viable therapeutic strategies for HD. To accomplish this, we are using novel and highly sensitive immunoprecipitation and flow cytometry (IP-FCM) protein detection assays, specific for the N586 neoepitope of HTT, to evaluate the in vivo persistence of N586 in HD model mice. If N586 is detected, it is likely that it is itself toxic and promoting its degradation may be beneficial. Conversely, if it is not detected, N586 cleavage likely initiates a toxic degradation pathway and promoting its stability may be beneficial. The results of these studies have the potential to define new therapeutic strategies for HD that can be addressed more specifically than generalized C6 inhibition for the prevention of N586-mediated toxicity. The selective targeting of N586 toxicity, either to promote or prevent its degradation depending on our results, would ensure that therapeutic activity is restricted to HTT and reduce the potential for deleterious off-target effects
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Date Issued
2018
Identifier
CFH2000395, ucf:45801
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000395