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No association between polymorphisms in the BDNF gene and age at onset in Huntington disease
Maren Mai, Amer D Akkad, Stefan Wieczorek, Carsten Saft, Jürgen Andrich, Peter H Kraus, J?rg T Epplen, Larissa Arning
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-79
Abstract: Five selected tagging polymorphisms were genotyped across a 65 kb region comprising the BDNF gene in a well established cohort of 250 unrelated German HD patients.Addition of BDNF genotype variations or one of the marker haplotypes to the effect of CAG repeat lengths did not affect the variance of the AO.We were unable to verify a recently reported association between the functional Val66Met polymorphism in the BDNF gene and AO in HD. From our findings, we conclude that neither sequence variations in nor near the gene contribute significantly to the variance of AO.Conclusive evidence indicates that brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of Huntington disease (HD). As the protein huntingtin (htt) directly modulates the expression of neuron-restrictive silencer factor (NRSF)-controlled genes, wild type (wt) htt stimulates the production of BDNF, whereas mutant htt causes the opposite effect [1]. It has been shown recently in transgenic mice that BDNF has an impact on the age at onset (AO) and the severity of motor dysfunction by controlling survival of striatal projection neurons [2].The BDNF gene consists of five alternatively spliced 5' exons and one major 3' exon producing at least six BDNF transcripts leading to three pre-proprotein isoforms which differ in the lengths of the signal peptides. Sequence variations in BDNF may therefore lead to variations in gene expression or protein metabolism causing selective neuronal vulnerability. The single nucleotide polymorphism (SNP) rs6265, producing a valine-to-methionine substitution at codon 66 (Val66Met) in the human BDNF gene appears to exert an effect on intracellular trafficking and activity-dependent secretion of BDNF [3]. Furthermore, Met-BDNF carriers demonstrate substantial relative decreases in hippocampal volume, and Val/Met-BDNF affects the volume of gray matter in the cerebral neocortex of normal humans. Finally Met-BDNF is associated with volume reductions prima
Failure to confirm influence of Methyltetrahydrofolate reductase (MTHFR) polymorphisms on age at onset of Huntington disease
Wiebke Hansen, Carsten Saft, Jürgen Andrich, Thomas Müller, Stefan Wieczorek, J?rg T Epplen, Larissa Arning
Journal of Negative Results in BioMedicine , 2005, DOI: 10.1186/1477-5751-4-12
Abstract: There was no statistically significant impact on AO for HD patients, neither of MTHFR SNPs nor of the combinations thereof.Contrary to previously described evidence the A1298C polymorphism in the MTHFR gene does not appear to modulate AO of HD patients.Huntington disease (HD) is caused by expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the 5'-translated region of the IT15 gene on chromosome 4, which encode the protein huntingtin [1]. The expansions result in the formation of elongated proteins with a variety of new properties. The extent of the expansion is inversely correlated with the age of onset (AO). Nevertheless, large part of the variance in AO remains unexplained [2]. The pathogenesis of HD has been implicated to relate to different aspects of the homocysteine metabolism: Cystathionine [beta]-synthase (CBS) appears to bind specifically to huntingtin (htt) [3]. CBS deficiency is associated with homocystinuria, which affects various physiological systems, including the central nervous system. Homocysteine, one of the substrates of CBS accumulates in homocystinuria and is metabolized to homocysteate and homocysteine sulphinate, both components of which are amino acids with significant excitotoxic potential. In this context homocysteine was suggested to influence the pathogenesis of HD. Two common polymorphisms have been described in the MTHFR gene, both single nucleotide substitutions resulting in amino acid changes (C677T → Ala222Val and A1298C → Glu429Ala) [4,5]. Whereas C677T unequivocally affects enzyme function and has been associated with increased plasma homocysteine concentrations and an altered balance of folate metabolites [4], the functional relevance in vivo of the A1298C allele is less well defined. A1298C affects enzyme function in vitro to a lesser degree, and individuals carrying the variation have frequently normal homocysteine and plasma folate concentrations [6,7]. It is unclear whether the substitution affects folate me
Kalirin, a Key Player in Synapse Formation, Is Implicated in Human Diseases  [PDF]
Prashant Mandela,Xin-Ming Ma
Neural Plasticity , 2012, DOI: 10.1155/2012/728161
Abstract: Synapse formation is considered to be crucial for learning and memory. Understanding the underlying molecular mechanisms of synapse formation is a key to understanding learning and memory. Kalirin-7, a major isoform of Kalirin in adult rodent brain, is an essential component of mature excitatory synapses. Kalirin-7 interacts with multiple PDZ-domain-containing proteins including PSD95, spinophilin, and GluR1 through its PDZ-binding motif. In cultured hippocampal/cortical neurons, overexpression of Kalirin-7 increases spine density and spine size whereas reduction of endogenous Kalirin-7 expression decreases synapse number, and spine density. In Kalirin-7 knockout mice, spine length, synapse number, and postsynaptic density (PSD) size are decreased in hippocampal CA1 pyramidal neurons; these morphological alterations are accompanied by a deficiency in long-term potentiation (LTP) and a decreased spontaneous excitatory postsynaptic current (sEPSC) frequency. Human Kalirin-7, also known as Duo or Huntingtin-associated protein-interacting protein (HAPIP), is equivalent to rat Kalirin-7. Recent studies show that Kalirin is relevant to many human diseases such as Huntington’s Disease, Alzheimer’s Disease, ischemic stroke, schizophrenia, depression, and cocaine addiction. This paper summarizes our recent understanding of Kalirin function. 1. Kalirin Is a Rho Guanine Nucleotide Exchange Factor (GEF) Kalirin was discovered 15 years ago as a novel protein that interacts with the cytosolic carboxyl-terminal of peptidylglycine α-amidating monooxygenase (PAM), an integral membrane peptide processing enzyme [1]. We have made significant progress in understanding the functions of Kalirin; like the many other Rho-GEFs encoded in mammalian genomes, Kalirin promotes the exchange of GDP for GTP and thus stimulates the activity of specific Rho GTPases [2, 3]. Rho GTPases that regulate multiple cellular processes play a key role in transducing signals from extracellular stimuli to the intracellular pathways that play a pivotal role in the formation of dendritic spines and synaptic development [4–6]. 2. Multiple Kalirin Isoforms The mouse Kalirin gene (Kalrn) consists of 65 exons spanning >650?kb of the genome; the presence of multiple promoters and transcriptional start sites enables the production of multiple functional isoforms of Kalirin [7–9]. Each Kalirin isoform is composed of a unique collection of domains (Figure 1). Major Kalirin isoforms including Kalirin-7, -9, and -12 are generated through the use of alternative 3′ exons [8]. The major isoforms share some common
The V471A Polymorphism in Autophagy-Related Gene ATG7 Modifies Age at Onset Specifically in Italian Huntington Disease Patients  [PDF]
Silke Metzger, Carolin Walter, Olaf Riess, Raymund A. C. Roos, J?rgen E. Nielsen, David Craufurd, REGISTRY Investigators of the European Huntington’s Disease Network , Huu Phuc Nguyen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068951
Abstract: The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.
PGC-1alpha as modifier of onset age in Huntington disease
Elahe Taherzadeh-Fard, Carsten Saft, Jürgen Andrich, Stefan Wieczorek, Larissa Arning
Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-10
Abstract: Huntington Disease (HD) is an autosomal-dominant disorder due to lesions in the striatum that cause involuntary choreiform movements and progressive behavioral and cognitive impairment. The underlying mutation is an expansion of an unstable CAG repeat in the HD gene resulting in an expanded polyglutamine tract in huntingtin protein (Htt) [1]. HD shows highly variable clinical expression, as exemplified by the wide variation of AO. The strong inverse relationship between AO and number of CAG repeats is well-defined. Yet, there is substantial variation in AO that is not explained by the HD repeat [2-6].To date, several genetic modifiers of HD have been described in independent studies. All of these modifiers relate to various mechanisms implicated in HD pathology such as excitotoxicity, dopamine toxicity, metabolic impairment, transcription deregulation, protein misfolding and oxidative stress [5,7-11]. Additionally, genomewide linkage scans revealed potential loci that may contain genes that modify AO [12-14].Increasing evidence implicates mitochondrial dysfunction and metabolic impairment in HD pathology [for review see [15]]. In particular, PGC-1alpha (peroxisome proliferator-activated receptor [PPAR]-g coactivator 1a) as a key transcriptional co-regulator is an important mediator in protecting neurons against oxidative damage and seems to be involved in HD pathogenesis. PGC-1alpha induces the transcription of cellular programs regulating mitochondrial respiration, oxidative stress defense and adaptive thermogenesis [16]. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD [17-19]. Altered PGC-1alpha function may, therefore, contribute to HD pathogenesis.A total of 15 single nucleotide polymorphisms (SNPs) in the peroxisome proliferators-activated receptor γ coactivator 1 α (PPARGC1A) gene (rs2970865, rs2970866, rs4383605, rs2946386, rs2970869, rs17576121, rs
Kalirin12 interacts with dynamin
Xiaonan Xin, Chana A Rabiner, Richard E Mains, Betty A Eipper
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-61
Abstract: The IgFn domain of Kalirin12, not present in other Kalirin isoforms, binds dynamin1 and dynamin2. An inactivating mutation in the GTPase domain of dynamin diminishes this interaction and the isolated GTPase domain of dynamin retains the ability to bind Kalirin12. Co-immunoprecipitation demonstrates an interaction of Kalirin12 and dynamin2 in embryonic brain. Purified recombinant Kalirin-IgFn domain inhibits the ability of purified rat brain dynamin to oligomerize in response to the presence of liposomes containing phosphatidylinositol-4,5-bisphosphate. Consistent with this, expression of exogenous Kalirin12 or its IgFn domain in PC12 cells disrupts clathrin-mediated transferrin endocytosis. Similarly, expression of exogenous Kalirin12 disrupts transferrin endocytosis in cortical neurons. Expression of Kalirin7, a shorter isoform which lacks the IgFn domain, was previously shown to inhibit clathrin-mediated endocytosis; the GTPase domain of dynamin does not interact with Kalirin7.Kalirin12 may play a role in coordinating Rho GTPase-mediated changes in the actin cytoskeleton with dynamin-mediated changes in membrane trafficking.The human genome encodes sixty-nine GDP/GTP exchange factors (GEFs) for small GTPases of the Rho subfamily [1,2]. All share the ability to remove GDP from target Rho proteins, allowing GTP to bind so that downstream effectors can be activated. In addition to having two RhoGEF domains, the Kalirin/Trio subfamily is unique in its use of multiple protein/protein and protein/lipid interaction modules (Fig. 1A). Kalirin7, the most prevalent isoform in adult brain, begins with a Sec14p domain, includes multiple spectrin-like repeats and ends with a PDZ binding motif. Kalirin7 is concentrated at the post-synaptic density (PSD) and is necessary for spine maturation, maintenance and function [3-7]. Kalirin12, the largest isoform, is most prevalent during embryonic development, but is also present in adult neurons [8,9].Features unique to Kalirin12 inclu
Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease  [PDF]
Tianle Chen,Yuanjia Wang,Yanyuan Ma,Karen Marder,Douglas R. Langbehn
Journal of Probability and Statistics , 2012, DOI: 10.1155/2012/375935
Abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone. 1. Introduction Huntington’s disease (HD) is a severe, autosomal dominantly inherited neurodegenerative disorder that affects motor, cognitive, and psychiatric function and is uniformly fatal. HD is caused by the expansion of CAG trinucleotide repeats at the huntingtin gene (IT15) [1, 2]. Affected individuals typically begin to show motor signs around 30–50 years of age and typically die 15–20 years after the disease onset [3]. Despite identification of the causative gene, there is currently no treatment that modifies disease progression. One large genetic epidemiological study of HD, the Cooperative Huntington’s Observational Research Trial (COHORT), including 42 Huntington study group research centers in North America and Australia, was initiated in 2005 and concluded in 2011 [4–6]. Participants in COHORT (probands) underwent a clinical evaluation and DNA from whole blood was genotyped for the length of the CAG-repeat huntingtin mutation. Since 2005, COHORT probands from sites with IRB approval have participated in family history interviews and have provided information on HD affection status in their family members. While CAG repeat length is ascertained in probands, the high cost of conducting in-person interviews of family members prevents the collection of all family members’ blood samples. However, family
The gene coding for PGC-1α modifies age at onset in Huntington's Disease
Patrick Weydt, Selma M Soyal, Cinzia Gellera, Stefano DiDonato, Claus Weidinger, Hannes Oberkofler, G Bernhard Landwehrmeyer, Wolfgang Patsch
Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-3
Abstract: Huntington's disease (HD [MIM 143100]; http://www.ncbi.nlm.nih.gov/Omim/ webcite) is one of the most common autosomal-dominant inherited neurodegenerative disorders. Clinically HD is characterized by motor and cognitive impairment, accompanied by a variable degree of personality change and psychiatric illness[1]. Advanced stages of HD are characterized by severe emaciation, despite a strong appetite and increased caloric intake[2,3]. HD is relentlessly progressive and patients succumb to the disease typically 10–25 years after disease onset[1]. In 1993, a CAG trinucleotide repeat expansion encoding an elongated polyglutamine tract in the huntingtin (HTT) protein was found to cause HD[4]. The number of CAG repeats in the htt gene is the most important, but not the only determinant of age at onset of HD. Depending on the populations studied, the number of CAG repeats in htt accounts for up to 73% of the variance in age at onset[5]. The remaining variation is strongly heritable[6]. Hence, modifier genes must contribute to the variability in age at onset of HD. The genetic modifiers identified so far include the huntingtin associated protein 1 (HAP1) gene and the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene [7-9]. The MAPS study, a genome-wide scan for modifier genes of age at onset using micro-satellite markers at a 10-cM density, suggested linkage at chromosomes 4p16, 6p21-23 and 6q24-26 and more marginal associations at several other sites, including 4p15 (marker D4S3403)[10].Recently, two independent groups presented evidence that the transcriptional co-regulator peroxisome proliferator-activated receptor γ (PPARγ) coactiavtor 1α (PGC-1α) plays a role in the neurodegeneration of HD [11-13]. PGC-1α regulates the expression of mitochondrial OXPHOS genes and endogenous antioxidants[14,15]. Mutant but not wild-type HTT down regulates the expression of this gene set[11,12]. Lack of PGC-1α expression produces a HD-like phenotype in mice and over-expression of PGC-
Polyglutamine Expansion Mutation Yields a Pathological Epitope Linked to Nucleation of Protein Aggregate: Determinant of Huntington's Disease Onset  [PDF]
Keizo Sugaya, Shiro Matsubara, Yasuhiro Kagamihara, Akihiro Kawata, Hideaki Hayashi
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000635
Abstract: Polyglutamine (polyQ) expansion mutation causes conformational, neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. These diseases are characterized by the aggregation of misfolded proteins, such as amyloid fibrils, which are toxic to cells. Amyloid fibrils are formed by a nucleated growth polymerization reaction. Unexpectedly, the critical nucleus of polyQ aggregation was found to be a monomer, suggesting that the rate-limiting nucleation process of polyQ aggregation involves the folding of mutated protein monomers. The monoclonal antibody 1C2 selectively recognizes expanded pathogenic and aggregate-prone glutamine repeats in polyQ diseases, including Huntington's disease (HD), as well as binding to polyleucine. We have therefore assayed the in vitro and in vivo aggregation kinetics of these monomeric proteins. We found that the repeat-length-dependent differences in aggregation lag times of variable lengths of polyQ and polyleucine tracts were consistently related to the integration of the length-dependent intensity of anti-1C2 signal on soluble monomers of these proteins. Surprisingly, the correlation between the aggregation lag times of polyQ tracts and the intensity of anti-1C2 signal on soluble monomers of huntingtin precisely reflected the repeat-length dependent age-of-onset of HD patients. These data suggest that the alterations in protein surface structure due to polyQ expansion mutation in soluble monomers of the mutated proteins act as an amyloid-precursor epitope. This, in turn, leads to nucleation, a key process in protein aggregation, thereby determining HD onset. These findings provide new insight into the gain-of-function mechanisms of polyQ diseases, in which polyQ expansion leads to nucleation rather than having toxic effects on the cells.
Atypical Parkinsonism Revealing a Late Onset, Rigid and Akinetic Form of Huntington's Disease
A. Ciammola,J. Sassone,B. Poletti,N. Mencacci,R. Benti,V. Silani
Case Reports in Neurological Medicine , 2011, DOI: 10.1155/2011/696953
Abstract: Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized in over 90 percent of cases by chorea as the presenting motor symptom. We report a 54-year-old male who presented with Parkinsonism as the initial symptom of the disease. Genetic analysis revealed expansion of 40 CAG repeats, and brain MRI showed both severe caudate nuclei and cortical atrophy. Single-photon emission computed tomography (SPECT) imaging of the dopamine transporter showed nigrostriatal pathway degeneration. Here, we also describe his 2 years of clinical followup after ensuing dopaminergic stimulation.
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