Pathogenic insights from Huntington's disease-like 2 and other Huntington's disease genocopies.

PURPOSE OF REVIEW: Huntington's disease-like 2 (HDL2) is a rare, progressive, autosomal dominant neurodegenerative disorder that genetically, clinically, and pathologically closely resembles Huntington's disease. We review HDL2 pathogenic mechanisms and examine the implications of these mechanisms for Huntington's disease and related diseases. RECENT FINDINGS: HDL2 is caused by a CTG/CAG repeat expansion in junctophilin-3. Available data from cell and animal models and human brain suggest that HDL2 is a complex disease in which transcripts and proteins expressed bidirectionally from the junctophilin-3 locus contribute to pathogenesis through both gain-and loss-of-function mechanisms. Recent advances indicate that the pathogenesis of Huntington's disease is equally complex, despite the emphasis on toxic gain-of-function properties of the mutant huntingtin protein. SUMMARY: Studies examining in parallel the genetic, clinical, neuropathological, and mechanistic similarities between Huntington's disease and HDL2 have begun to identify points of convergence between the pathogenic pathways of the two diseases. Comparisons to other diseases that are phenotypically or genetically related to Huntington's disease and HDL2 will likely reveal additional common pathways. The ultimate goal is to identify shared therapeutic targets and eventually develop therapies that may, at least in part, be effective across multiple similar rare diseases, an essential approach given the scarcity of resources for basic and translational research.

Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality.

We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (DstGt) mice. Compound heterozygotes showed a typical dt phenotype with sensory degeneration and progressive motor symptoms. DNA sequencing analysis identified a nonsense mutation within the spectrin repeats of the plakin domain. The novel mutant allele was named dt23Rbrc. Motor abnormalities in homozygous dt23Rbrc/dt23Rbrc mice are not as severe as homozygous DstGt/DstGt mice. Histological analyses showed abnormal neurofilament (NF) accumulation in the nervous system of homozygous dt23Rbrc/dt23Rbrc mice, which is characteristic of the dt phenotype. We mapped the distribution of abnormal NF-accumulated neurons in the brain and found that they were located specifically in the brainstem, spinal cord, and in regions such as the vestibular nucleus, reticular nucleus, and red nucleus, which are implicated in posture and motor coordination pathways. The quantification of abnormal NF accumulation in the cytoplasm and spheroids (axons) of neurons showed that abnormal NF immunoreactivity was lower in homozygous dt23Rbrc/dt23Rbrc mice than in homozygous DstGt/DstGt mice. Therefore, we have identified a novel hypomorphic allele of dt, which causes histological abnormalities in the central nervous system that may account for the abnormal motor phenotype. This novel spontaneously occurring mutant may become a good model of hereditary sensory and autonomic neuropathy type 6, which is caused by mutations in the human DST gene.

Neurodegeneration beyond the primary visual pathways in a population with a high incidence of normal-pressure glaucoma.

PURPOSE: Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma. METHODS: We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage. RESULTS: Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p < 0.05; family-wise error-corrected) comprising fibres of both the optic radiation and the forceps major. Additional analysis confirmed bilateral involvement of the optic radiations and forceps major and additionally revealed damage to the corpus callosum and parietal lobe (p < 0.09; family-wise error-corrected). The region of interest-based analysis revealed a positive association between Fractional Anisotropy of the optic radiation and optic nerve damage. CONCLUSIONS: In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.

Astrocytes and disease: a neurodevelopmental perspective.

Astrocytes are no longer seen as a homogenous population of cells. In fact, recent studies indicate that astrocytes are morphologically and functionally diverse and play critical roles in neurodevelopmental diseases such as Rett syndrome and fragile X mental retardation. This review summarizes recent advances in astrocyte development, including the role of neural tube patterning in specification and developmental functions of astrocytes during synaptogenesis. We propose here that a precise understanding of astrocyte development is critical to defining heterogeneity and could lead advances in understanding and treating a variety of neuropsychiatric diseases.

Alteraciones cognitivas en el trastorno bipolar: posibles etilogías / Cognitive alterations in bipolar disorder: possible etiologies

Diversos estudios científicos sugieren la posibilidad de cambios estructurales y/o funcionales en el cerebro de los sujetos con diagnóstico de trastorno bipolar (TBP). A su vez, estos individuos presentan déficits en un alto rango de pruebas neuropsicológicas, tanto durante los episodios agudos como en autimia, que se correlacionan también con el número de episodios y con la duración de la enfermedad. Las alteraciones halladas más frecuentemente consisten en déficits atencionales, en aprendizaje y memoria y en funciones ejecutivas. Esta revisión se propone estudiar 6 causas que potencialmente podrían estar implicadas en la aparición de las deficiencias cognitivas en los sujetos con TBP: 1) iatrogénica y/o abuso de sustancias, 2)cambios funcionales agudos asociados con depresión y/o manía, 3) lesiones estructurales permanentes de origen neurodegenerativo, 4) lesiones estructurales permanentes de origen en el neurodesarrollo, 5) cambios funcionales permanentes de origen genético, y 6) cambios funcionales permanentes secundarios a influencias del entorno. Se concluye que las diversas alteraciones cognitivas presentes en los individuos con TBP serían consecuencia de la interacción y la combinación aleatoria de los distintos factores mencionados.(AU)

Different scientific studies suggest the possibility of structural and/or functional changes in the brain of people whit diagnosis of Bipolar Disorder. Besides that, these people show deficits in a large number of neuro psychological test, both in acute episodes and in eutimia. Deficits are also correlated with the number of episodes and the duration of the illness. The most frequent alterations founded were deficits in attention, learning and memory and executive functions. This review proposes the study of six causes that potentially could be implicated in the emergence of the cognitive deficits in people whit bipolar disorder: 1) iatrogenic and/or substance abuse; 2) acute functional changes related to depression and/or mania; 3) permanent structural injuries neurodegenertive in origin; 4) permanent structural injuries neurodevelopmental in origin; 5) permanent functional changes of genetic origin; 6) permanent functional changes as a consequence of environmental influence. Our conclusion is that different cognitive alterations in people with bipolar disorder are the consequence of the interaction and random combination of different factors mentioned above.(AU)

Alteraciones cognitivas en el trastorno bipolar: posibles etilogías / Cognitive alterations in bipolar disorder: possible etiologies

Diversos estudios científicos sugieren la posibilidad de cambios estructurales y/o funcionales en el cerebro de los sujetos con diagnóstico de trastorno bipolar (TBP). A su vez, estos individuos presentan déficits en un alto rango de pruebas neuropsicológicas, tanto durante los episodios agudos como en autimia, que se correlacionan también con el número de episodios y con la duración de la enfermedad. Las alteraciones halladas más frecuentemente consisten en déficits atencionales, en aprendizaje y memoria y en funciones ejecutivas. Esta revisión se propone estudiar 6 causas que potencialmente podrían estar implicadas en la aparición de las deficiencias cognitivas en los sujetos con TBP: 1) iatrogénica y/o abuso de sustancias, 2)cambios funcionales agudos asociados con depresión y/o manía, 3) lesiones estructurales permanentes de origen neurodegenerativo, 4) lesiones estructurales permanentes de origen en el neurodesarrollo, 5) cambios funcionales permanentes de origen genético, y 6) cambios funcionales permanentes secundarios a influencias del entorno. Se concluye que las diversas alteraciones cognitivas presentes en los individuos con TBP serían consecuencia de la interacción y la combinación aleatoria de los distintos factores mencionados.

Different scientific studies suggest the possibility of structural and/or functional changes in the brain of people whit diagnosis of Bipolar Disorder. Besides that, these people show deficits in a large number of neuro psychological test, both in acute episodes and in eutimia. Deficits are also correlated with the number of episodes and the duration of the illness. The most frequent alterations founded were deficits in attention, learning and memory and executive functions. This review proposes the study of six causes that potentially could be implicated in the emergence of the cognitive deficits in people whit bipolar disorder: 1) iatrogenic and/or substance abuse; 2) acute functional changes related to depression and/or mania; 3) permanent structural injuries neurodegenertive in origin; 4) permanent structural injuries neurodevelopmental in origin; 5) permanent functional changes of genetic origin; 6) permanent functional changes as a consequence of environmental influence. Our conclusion is that different cognitive alterations in people with bipolar disorder are the consequence of the interaction and random combination of different factors mentioned above.

Functional genomics approaches to neurodegenerative diseases.

Many of the neurodegenerative diseases that afflict humans are characterised by the protein aggregation in neurons. These include complex diseases like Alzheimer's disease and Parkinson's disease, and Mendelian diseases caused by polyglutamine expansion mutations [like Huntington's disease (HD) and various spinocerebellar ataxias (SCAs), like SCA3]. A range of functional genomic strategies have been used to try to elucidate pathways involved in these diseases. In this minireview, I focus on how modifier screens in organisms from yeast to mice may be of value in helping to elucidate pathogenic pathways.

Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery.

BACKGROUND: Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is distinct from fragile X syndrome (FXS) in its molecular aetiology and clinical presentation. The primary features of FXTAS are late-onset intention tremor and gait ataxia. Associated features include parkinsonism, neuropsychological dysfunction, autonomic dysfunction and peripheral neuropathy. AIM: To investigate the usefulness of a quantitative neurological test battery implemented through the CATSYS instrument to identify preclinical symptoms of FXTAS. METHODS: Both premutation carriers with 70-199 repeats (62 men) and their low-repeat allele carrier siblings (27 men), identified through families with an individual affected with FXS, were tested. RESULTS: As expected, because of its sensitivity, use of the instrument allowed identification of tremor in 23% of men who had not self-reported tremor, and ataxia in 30% of men who had not self-reported ataxia. Among subjects with self-reported tremor and ataxia, we found significant concordance between measures of the CATSYS system and the self-report. CONCLUSION: Rates of these traits among premutation carriers and low-repeat allele carrier siblings could be identified, and are presented in this paper, along with the minimum estimates of age-related prevalence.

Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases.

Spinocerebellar Ataxia type 1 (SCA1) and Huntington's disease (HD) are two polyglutamine disorders caused by expansion of a CAG repeat within the coding regions of the Ataxin-1 and Huntingtin proteins, respectively. While protein folding and turnover have been implicated in polyglutamine disorders in general, many clinical and pathological differences suggest that there are also disease-specific mechanisms. Taking advantage of a collection of genetic modifiers of expanded Ataxin-1-induced neurotoxicity, we performed a comparative analysis in Drosophila models of the two diseases. We show that while some modifier genes function similarly in SCA1 and HD Drosophila models, others have model-specific effects. Surprisingly, certain modifier genes modify SCA1 and HD models in opposite directions, i.e. they behave as suppressors in one case and enhancers in the other. Furthermore, we find that modulation of toxicity does not correlate with alterations in the formation of neuronal intranuclear inclusions. Our results point to potential common therapeutic targets in novel pathways, and to genes and pathways responsible for differences between Ataxin-1 and Huntingtin-induced neurodegeneration.

Polyglutamine diseases: emerging concepts in pathogenesis and therapy.

Polyglutamine diseases are a family of neurodegenerative conditions that each derive from a CAG triplet repeat expansion in a specific gene. This produces a pathogenic protein that contains a critically expanded tract of glutamines. These prototypical protein misfolding disorders include Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and several spinocerebellar ataxias. This article reviews the emerging concepts in pathogenesis and therapy. Key ideas include the role of proteolytic cleavage, the importance of conformational change in the pathogenic proteins, the role of protein aggregation and the importance of transcriptional and metabolic disturbances. The relative role of functional perturbation in a target protein induced by a polyglutamine expansion is also discussed. Therapeutic strategies include counteracting cellular perturbations and direct targeting of polyglutamine protein expression, cleavage or conformation.

Beta-amyloid, oxidative stress and down syndrome.

Down syndrome (DS) provides a model for studying important aspects of Alzheimer disease (AD). Chromosome 21 contains several genes that have been implicated in neurodegenerative mechanisms. These include Cu/Zn superoxide dismutase (SOD-1), Ets-2 transcription factors, Down Syndrome Critical Region 1 (DSCR1) stress-inducible factor, and the amyloid precursor protein (APP). The accumulation of Abeta plaques is progressive across the lifespan in DS. Overexpression of APP in the obligate region for DS is associated with abundant Abeta plaques and tangles consistent with Braak stage V-VI. Intraneuronal Abeta in DS appears to trigger a pathological cascade leading to oxidative stress and a neurodegeneration typical of AD. There are suggestions that an increase in subcellular processing of APP and factors related to membrane APP cleavage favor the secretion of Abeta with age in DS. A misbalance between SOD-1 and glutathione perioxidase activity in DS has been linked to free radical generation. Ets-2 and DSCR1 overexpression in DS has been linked to cell degeneration. Age-related accumulation of somatic DNA mutations in both DS and AD contribute to oxidative stress that exacerbates the imbalance in gene expression. This leads to enhanced Abeta deposition and further neuronal vulnerability. The consequence of these factors and their temporal relationships is likely to be the subject of future research. Since the pathological processes leading to AD are seen across the lifespan in DS, an opportunity is afforded for early pharmacological intervention in the disorder.

Untangling the tau gene association with neurodegenerative disorders.

Pathological tau protein inclusions have long been recognized to define the diverse range of neurodegenerative disorders called the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration. Mutations in the tau gene, MAPT, cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and common variation in MAPT is strongly associated with the risk of PSP, corticobasal degeneration and, to a lesser extent, AD and Parkinson's disease (PD), implicating the involvement of tau in common neurodegenerative pathway(s). This review will discuss recent work towards the unravelling of the functional basis of this MAPT gene association. The region of chromosome 17q21 containing MAPT locus is characterized by the complex genomic architecture, including a large inversion that leads to a bipartite haplotype architecture, an inversion-mediated deletion and multiplications resulting from non-allelic homologous recombination between the MAPT family of low-copy repeats.

Saitohin, which is nested in the tau locus and confers allele-specific susceptibility to several neurodegenerative diseases, interacts with peroxiredoxin 6.

Saitohin is a gene unique to humans and their closest relatives, the function of which is not yet known. Saitohin contains a single polymorphism (Q7R), and its Q and R alleles belong to the H1 and H2 tau haplotype, respectively. The Saitohin Q allele confers susceptibility to several neurodegenerative diseases. To get a handle on Saitohin function, we used it as a bait in a yeast two-hybrid screen. By this assay and subsequent co-immunoprecipitation and glutathione S-transferase pull-down assays, we discovered and confirmed that Saitohin interacts with peroxiredoxin 6, a unique member of that family that is bifunctional and the levels of which increase in Pick disease. The strength of the interaction appeared to be allele-specific, giving the first distinction between the two forms of Saitohin.

Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury.

Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult. It is shown that a mild insult initiates progressive neurodegeneration that leads to cystic infarcts, which can be prevented by inactivating the IL-1R1. The IL-1R1 null mice also show preserved sensorimotor function at 1 month's recovery. The mild insult induces multiple proinflammatory cytokines and activates microglia, and these responses are dramatically curtailed in mice lacking the IL-1R1. Importantly, the neuroinflammation precedes the progressive enlargement of the infarct, suggesting that the inflammation is causal rather than a consequence of the brain damage. These findings show that abrogating the inflammation consequent to a mild H/I insult will prevent brain damage and preserve neurological function. Additionally, these data incriminate the IL-1R1 as a master proinflammatory cytokine receptor.

Hereditary causes of disturbed iron homeostasis in the central nervous system.

Iron is essential for oxidation-reduction catalysis and bioenergetics; however, unless appropriately shielded, this metal plays a crucial role in the formation of toxic oxygen radicals that can attack all biological molecules. Organisms are equipped with specific proteins designed for iron acquisition, export and transport, and storage, as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. This review describes several hereditary iron-overloading conditions that are confined to the brain. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich's ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron-sulfur cluster formation, and the neurologic and cardiac manifestations of Friedreich's ataxia are due to iron-mediated mitochondrial toxicity. Patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus. Finally, aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by loss-of-function mutations in ceruloplasmin gene that leads to misregulation of both systemic and central nervous system iron trafficking. Affected individuals suffer from extrapyramidal signs, cerebellar ataxia, progressive neurodegeneration of retina, and diabetes mellitus. Excessive iron depositions are found in the brain, liver, pancreas, and other parenchymal cells, but plasma iron concentrations are decreased. These conditions are not common, but awareness about them is important for differential diagnosis of various neurodegenerative disorders.

Genes and parkinsonism.

Genetic studies in families with mendelian inheritance of Parkinson's disease (PD) have reported the cloning of several disease-associated genes. These studies of rare familial forms of the disease have cast doubt on our understanding of the role of genetics in typical PD and have complicated the classification of the disorder. However, this genetic information might help us to construct a hypothesis for the pathogenetic processes that underlie PD. In this review we describe the molecular genetics of PD as currently understood to help explain the pathways that underlie neurodegeneration.