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PubMed2000

N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease.

The present study examines N-myc and c-myc protein expression with Western blotting and single and double-labeling immunohistochemistry in the hippocampus in Alzheimer disease (AD), the striatum in Huntington disease (HD) and the substantia nigra in Parkinson disease (PD). No modifications in the N-myc and c-myc expression are found in hippocampal neurons in AD, striatal neurons in HD, and pigmented neurons of the substantia nigra in PD. Yet punctate synaptic-like N-myc immunoreactivity, matching enhanced synaptophysin expression, occurs in diffuse plaques, but not in dystrophic neurites of neuritic plaques. In contrast, c-myc immunoreactivity is found in dystrophic neurites, but not in aberrant sproutings of neuritic plaques, as shown by double-labeling immunohistochemistry to c-myc and phosphorylated tau or phosphorylated neurofilament epitopes, and to c-myc and GAP-43, respectively. Strong N-myc and c-myc are observed in reactive astrocytes in AD, HD and PD, as revealed by double-labeling with N-myc or c-myc and GFAP. Finally, no relationship is found between nuclear DNA fragmentation and increased N-myc or c-myc expression in individual cells. These results demonstrate that neuron death in AD, HD and PD is not associated with modifications in the steady-state expression of N-myc and c-myc in individual neurons, and that neurofibrillary degeneration and Lewy body formation are not accompanied by increased immunoreactivity to these transcription factors. Increased N-myc and c-myc expression in reactive astrocytes probably plays a role in reactive astrocytosis in human neurodegenerative disorders.

Aged↗

PubMed2004

Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.

Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.

Animals↗

PubMed2000

Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease.

Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.

Animals↗

PubMed2005

Proteomic analysis of protein expression and oxidative modification in r6/2 transgenic mice: a model of Huntington disease.

Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin on chromosome 4, has been unambiguously identified. On the other hand, the mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in energy metabolism of affected cells may cause oxidative damage, which has been proposed as one of the underlying molecular mechanisms that participate in the etiology of the disease. In our effort to investigate the extent of oxidative damage occurring at the protein level, we used a parallel proteomic approach to identify proteins potentially involved in processes upstream or downstream of the disease-causing huntingtin in a well established HD mouse model (R6/2 transgenic mice). We have demonstrated that the expression levels of dihydrolipoamide S-succinyltransferase and aspartate aminotransferase increase consistently over the course of disease (10-week-old mice). In contrast, pyruvate dehydrogenase expression levels were found to be decreased in 10-week-old HD transgenic mice compared with young (4-week-old) mice. Our experimental approach also led to the identification of oxidatively modified proteins. Six proteins were found to be significantly oxidized in old R6/2 transgenic mice compared with either young transgenic mice or non-transgenic mice. These proteins are alpha-enolase, gamma-enolase (neuron-specific enolase), aconitase, the voltage-dependent anion channel 1, heat shock protein 90, and creatine kinase. Because oxidative damage has proved to play an important role in the pathogenesis and the progression of Huntington disease, our results for the first time identify specific oxidatively modified proteins that potentially contribute to the pathogenesis of Huntington disease.

Aging↗

PubMed1984

The current state of research with peripheral tissues in Huntington disease.

Huntington disease is a neurological autosomal dominant disease of unknown origin and the search for a suitable diagnostic marker has been extended to the peripheral tissues. It is generally believed that a membrane defect exists in Huntington disease although the evidence is controversial. It is the aim of this review to examine the validity of these claims for each of the peripheral tissues and techniques involved, and it is not intended to include all other aspects of research into Huntington disease.

Antibody-Dependent Cell Cytotoxicity↗

PubMed2002

[The DNA test in the diagnosis of Huntington disease].

Huntington's disease is the most prominent basal ganglion disease. Huntington's gene, IT15, in chromosome 4p16.3, has 67 axons with 10,366 bp coding space and unstable CAG sequence that codes glutamine on 5' terminal. The molecular-genetic analysis of disease determined expansion of nucleotide repeated CAG sequences. In large Bosnian family with Huntington's disease specific DNA diagnosis of IT15 gene mutation is performed, according the wishes of one female member with "high genetic risk", that voluntarily accessed to DNA test in order to make plans for her own family "without risk" of pathologic gene transmission. A mutation in IT15 gene (number of CAG tandem repeats 46, size of DNA fragment 165 bp and 245 bp) is detected in DNA of her clinically affected brother. But, results of PCR analysis of her DNA sample showed 23 CAG tandem repeats (fragment size 180 bp) that excluded presence of Huntington's disease. We accentuate importance of DNA test in persons with "genetic risk", that are not gene carriers. In that case there are able to create own future without fear of pathological gene transmission.

Female↗

PubMed1983

Somatostatin is increased in the basal ganglia in Huntington disease.

Huntington disease (HD) is an autosomal dominant hereditary disorder characterized by premature cell death, predominantly in the neostriatum. Decreased concentrations of several neurotransmitters and neuropeptides have been reported in the basal ganglia in Huntington disease. We now report that concentrations of radioimmunoassayable somatostatin are increased in extracts of the caudate (mean +/- standard error of the mean, ng/gm net weight; 247 +/- 24 versus 85 +/- 11), putamen (275 +/- 48 versus 74 +/- 11), external globus pallidus (100 +/- 10 versus 27 +/- 6), and internal globus pallidus (108 +/- 21 versus 21 +/- 8) in the disease. The concentrations of immunoreactive substance P measured in the same extracts were markedly reduced in caudate (mean +/- standard error of the mean, pmol/gm wet weight; 25 +/- 3 versus 109 +/- 20), putamen (28 +/- 7 versus 88 +/- 28), external globus pallidus (39 +/- 9 versus 196 +/- 62), and internal globus pallidus (60 +/- 17 versus 263 +/- 39), as well as in both subdivisions of the substantia nigra. Gel permeation chromatography and high-performance liquid chromatography showed radioimmunoassayable somatostatin to include peptides with physicochemical properties of the tetradecapeptide somatostatin and larger substances, including somatostatin-28-like material. A single peak of immunoreactive substance P corresponding to synthetic substance P was found by high performance liquid chromatography. These results suggest that immunoassayable somatostatin-containing neuronal elements in the neostriatum and globus pallidus in Huntington disease are affected differentially by the disease process from neurons that contain immunoreactive substance P.

Adolescent↗

PubMed2005

A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease.

Huntington disease is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein huntingtin (Htt), which leads to its aggregation in nuclear and cytoplasmic inclusion bodies. We recently identified 52 loss-of-function mutations in yeast genes that enhance the toxicity of a mutant Htt fragment. Here we report the results from a genome-wide loss-of-function suppressor screen in which we identified 28 gene deletions that suppress toxicity of a mutant Htt fragment. The suppressors are known or predicted to have roles in vesicle transport, vacuolar degradation, transcription and prion-like aggregation. Among the most potent suppressors was Bna4 (kynurenine 3-monooxygenase), an enzyme in the kynurenine pathway of tryptophan degradation that has been linked directly to the pathophysiology of Huntington disease in humans by a mechanism that may involve reactive oxygen species. This finding is suggestive of a conserved mechanism of polyglutamine toxicity from yeast to humans and identifies new candidate therapeutic targets for the treatment of Huntington disease.

Autophagy↗

PubMed1992

Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

Huntington disease is a neurological movement disorder involving massive neuronal death in the caudate-putamen region of the brain. Neither preventive nor curative therapy exists for this disease. The implantation of cross-species striatal neural precursor cells into the lesioned striatum of nonhuman primates (baboons) reduced the abnormal movements seen in the disease model. These abnormal movements reappeared after immunological rejection of the implanted striatal cells and were not modified by transplantation with nonstriatal cells. These findings encourage further experimentation toward the use of cell sources other than human fetal cells in a potential clinical application to Huntington disease.

Animals↗

PubMed1996

Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease.

Huntington disease is a dominantly inherited, untreatable neurological disorder featuring a progressive loss of striatal output neurons that results in dyskinesia, cognitive decline, and, ultimately, death. Neurotrophic factors have recently been shown to be protective in several animal models of neurodegenerative disease, raising the possibility that such substances might also sustain the survival of compromised striatal output neurons. We determined whether intracerebral administration of brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, or ciliary neurotrophic factor could protect striatal output neurons in a rodent model of Huntington disease. Whereas treatment with brain-derived neurotrophic factor, nerve growth factor, or neurotrophin-3 provided no protection of striatal output neurons from death induced by intrastriatal injection of quinolinic acid, an N-methyl-D-aspartate glutamate receptor agonist, treatment with ciliary neurotrophic factor afforded marked protection against this neurodegenerative insult.

Animals↗

PubMed1999

Recent insights into the molecular pathogenesis of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene resulting in expression of an uninterrupted polyglutamine stretch within the N-terminus of its protein product huntingtin (htt). In this article we review the clinical, genetic, and neuropathological features of HD and discuss recent insights into the pathogenesis of HD. Examining the role of CAG repeat size on age of onset and penetrance in HD using a refined database of human HD patients has provided further support for the importance of the CAG repeat in the pathogenesis of HD and information leading to a predictive model for the likelihood of being affected by a specific age for a particular CAG expansion. In a YAC transgenic mouse model that replicates key elements of the HD phenotype, the development of selective striatal neurodegeneration is coincident with cleavage of htt and translocation of the N-terminal htt fragment into the nucleus. We also review in vitro evidence that htt is a substrate for cleavage by a group of cysteine proteases involved in apoptotic death-the caspases, and that caspase cleavage of htt results in the generation of a toxic N-terminal fragment. Inhibiting caspase cleavage of huntingtin eliminates the toxicity of the mutant htt protein. These results suggest that cleavage of huntingtin resulting in production of a truncated N-terminal fragment may be a crucial step in the pathogenesis of Huntington disease and that inhibition of this process may be a potential therapeutic strategy for this currently untreatable disorder.

Animals↗

PubMed2004

Propofol and remifentanil total intravenous anesthesia for a patient with Huntington disease.

Huntington disease presents many challenges for the anesthetist. Of primary importance is that these patients are at increased risk of pulmonary aspiration. The use of short-acting anesthetic drugs should, therefore, be advantageous in promoting the rapid return of protective airway reflexes. We report the first documented use, to date, of propofol and remifentanil total intravenous anesthesia in a patient with Huntington disease and demonstrate its efficacy and safety.

Adult↗

PubMed2003

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

Adolescent↗

PubMed1997

Multidisciplinary approach to management of a hereditary neurodegenerative disorder: Huntington disease.

Huntington Disease is a well known autosomal dominant inherited disease resulting in emotional problems, abnormalities of movement, and eventually dementia. It stands out as one of the most devastating illnesses, not only for its neurodegenerative progression but also for its impact on families. Care often becomes fragmented due to the person's response to symptoms and/or family breakdown. The successful interaction of health care disciplines working with Huntington Disease in our centers, namely, the family physicians, nursing, Genetics, Neurology, Psychiatry, Social Work, and Long Term Care has resulted in a comprehensive program of care for our patients and their families. This article will describe the history, structure and interaction of the multidisciplinary group. It will describe the difficulties we have overcome and offer suggestions for the implementation of similar programs for the care of people with other disorders.

Humans↗

PubMed1981

Joseph disease and Huntington disease: protein patterns in fibroblasts and brain.

Proteins were separated on two-dimensional acrylamide gels obtained from brain samples of patients with Joseph disease, Huntington disease (HD) and multiple sclerosis. Similar protein separations were made from cultured skin fibroblasts of Joseph disease patients. Two major classes of proteins, one with a MW of 50,000 probably representing the glial filamentous acidic protein, or another class with a MW of 40,000 (proteins Jc, Jd, L1 and L2) were increased in the cerebellum of six Joseph disease patients. The same protein species were abnormally increased in HD brains, mainly in the basal ganglia and frontal cortex. These identical classes of protein changes were present in two nosologically separate autosomal dominant neurological disorders, Joseph disease (a spinocerebellar degeneration) and HD (a basal ganglia and cerebral cortical degeneration) and may reflect a biochemical correlation of gliosis and neuronal disease. However, these changes may be evidence that the two diseases are allelic mutations of the same gene. The dominantly inherited spinocerebellar degenerations may result from a primary deficit of glial-neuronal interaction, resulting in neuronal loss but with a compensatory increase in the number of glial cells attempting to provide additional trophic-metabolic support.

Adult↗

PubMed2006

Early and transient alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease.

Huntington Disease (HD) is characterized by choreic involuntary movements and striatal vulnerability. A2A receptors expressed on GABAergic striatal neurons have been suggested to play a pathogenetic role. Previous data demonstrated the presence of an aberrant alteration of A2A receptor-dependent adenylyl cyclase in an in vitro model of the disease (striatal cells expressing mutant huntingtin) and in peripheral circulating cells of HD patients. Here, we investigated whether this dysfunction is present in the R6/2 HD transgenic mouse model, by analyzing striatal A2A receptor-binding and adenylyl cyclase activity at different developmental stages in comparison with age-matched wild type animals. A transient increase in A2A receptor density (Bmax) and A2A receptor-dependent cAMP production at early presymptomatic ages (7-14 postnatal days) was found. Both alterations normalized to control values starting from postnatal day 21. In contrast, A2A receptor mRNA, as detected by real time PCR, dramatically decreased starting from PND21 until late symptomatic stages (12 weeks of age). The discrepancy between A2A receptor expression and density suggests compensatory mechanisms. These data, reproducing ex vivo the previous observations in vitro, support the hypothesis that an alteration of A2A receptor signaling is present in HD and might represent an interesting target for neuroprotective therapies.

Adenylyl Cyclases↗

PubMed1983

Two models for a maternal factor in the inheritance of Huntington disease.

Huntington disease is a classic example of an autosomal dominant trait. Over the years, however, a number of investigators have reported anomalies regarding the age of onset of the disease that are inconsistent with this paradigm. We propose two models in which a maternal factor--cytoplasmic in one case, autosomal or X-linked in the other--acts to delay onset in a manner consistent with the previously reported anomalies. Relevant data from the Huntington's Disease Research Roster are presented that reinforce and extend the previous observations.

Adolescent↗

PubMed2005

Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease.

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a toxic gain of function in the huntingtin (htt) protein. The contribution of wild-type htt function to the pathogenesis of HD is currently uncertain. To assess the role of wild-type htt in HD, we generated YAC128 mice that do not express wild-type htt (YAC128-/-) but express the same amount of mutant htt as normal YAC128 mice (YAC128+/+). YAC128-/- mice perform worse than YAC128+/+ mice in the rotarod test of motor coordination (P = 0.001) and are hypoactive compared with YAC128+/+ mice at 2 months (P = 0.003). Striatal neuropathology was not clearly worse in YAC128-/- mice compared with YAC128+/+ mice. There was no significant effect of decreased wild-type htt on striatal volume, neuronal counts or DARPP-32 expression but a modest worsening of striatal neuronal atrophy was evident (6%, P = 0.03). The testis of YAC128+/+ mice showed atrophy and degeneration, which was markedly worsened in the absence of wild-type htt (P = 0.001). YAC128+/+ mice also showed a male specific deficit in survival compared with WT mice which was exacerbated by the loss of wild-type htt (12-month-male survival, P < 0.001). Overall, we demonstrate that the loss of wild-type htt influences motor dysfunction, hyperkinesia, testicular degeneration and impaired lifespan in YAC128 mice. The mild effect of wild-type htt on striatal phenotypes in YAC128 mice suggests that the characteristic striatal neuropathology in HD is caused primarily by the toxicity of mutant htt and that replacement of wild-type htt will not be an adequate treatment for HD.

Animals↗