Kegg Pathway: Huntington's disease

Neurosci Bull. 2009 Dec; 25(6): 343-352
Kalonia H, Kumar P, Kumar A, Nehru B

Objective The neuroprotective roles of cyclooxygenase (COX) and lipooxygenase (LOX) inhibitors have been well documented. Quinolinic acid (QA) is a well-known excitotoxic agent that could induce behavioral, morphological and biochemical alterations similar with symptoms of Huntington's disease (HD), by stimulating NMDA receptors. However, the exact roles of COX and LOX inhibitors in HD have not yet been explained. The present study aims to elucidate the effects of caffeic acid (a specific inhibitor for LOX), rofecoxib (a specific inhibitor for COX-2), and their combination in ameliorating QA-induced neurotoxicity in rats. Methods QA was injected into the right striatum of rats to induce neurotoxicity. Caffeic acid and rofecoxib were then orally administered separately. In the combination study, caffeic acid and rofecoxib were administered together. After that, a series of behavioral assessments were conducted to determine the effects of caffeic acid and rofecoxib, respectively, and the co-effect of caffeic acid and rofecoxib, against QA-induced neurotoxicity. Results Intrastriatal QA administration (300 nmol) not only induced a significant reduction in body weight and motor incoordination, but also altered the redox status (decreased glutathione and increased oxidized glutathione level) in striatum, as compared to the sham group. Moreover, chronic treatment with caffeic acid (5 mg/kg and 10 mg/kg, respectively, p.o.) or rofecoxib (10 mg/kg, p.o.) could significantly attenuate QA-induced behavioral alterations and restore the redox status in striatum. However, at the dose of 2.5 mg/kg, caffeic acid did not show any significant effects on these parameters in QA-treated rats. Furthermore, the combination of rofecoxib (10 mg/kg) and caffeic acid (5 mg/kg) could significantly protect against QA neurotoxicity. Conclusion The in vivo study indicates that excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione. Moreover, the LOX and the COX pathways may be both involved in quinolinic-induced neurotoxicity, which provides a promising target for HD treatment.

Cell Cycle. 2009 Dec 17; 8(23):
Glinskii AB, Ma J, Ma S, Grant D, Lim CU, Sell S, Glinsky GV

Meta-analysis of genomic coordinates of SNP variations identified in genome-wide association studies (GWAS) of up to 712,253 samples (comprising 221,158 disease cases, 322,862 controls, and 168,233 case/control subjects of obesity GWAS) reveals that 39% of SNPs associated with 22 common human disorders are located within intergenic regions. Chromatin-state maps based on H3K4me3-H3K36me3 signatures show that many intergenic disease-linked SNPs are located within the boundaries of the K4-K36 domains, suggesting that SNP-harboring genomic regions are transcribed. Here we report identification of 13 trans-regulatory RNAs (transRNAs) 100 to 200 nucleotides in length containing intergenic SNP sequences associated with Crohn's disease, rheumatoid arthritis, type 1 diabetes, vitiligo, hypertension and multiple types of epithelial malignancies (prostate, breast, ovarian and colorectal cancers). We demonstrate that NALP1 loci intergenic SNP sequence, rs2670660, is expressed in human cells and may contribute to clinical manifestations of autoimmune and autoimflammatory phenotypes by generating distinct allelic variants of transRNAs. Stable expression of allele-specific sense and anti-sense variants of transRNAs markedly alters cellular behavior, affect cell cycle progression, and interfere with monocyte/macrophage transdifferentiation. On a molecular level, forced expression of allele-specific sense and anti-sense variants of transRNAs asserts allele-specific genome-wide effects on abundance of hundreds microRNAs and mRNAs. Using lentiviral gene transfer, microarray and Q-RT-PCR technologies, we identify rs2670660 allele-specific gene expression signatures (GES) which appear useful for detecting the activated states of innate immunity/inflammasome pathways in approximately 700 clinical samples from 185 control subjects and 350 patients diagnosed with 9 common human disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, Huntington disease, autism, Alzheimer disease, obesity, prostate and breast cancers. Microarray analysis of clinical samples demonstrates that rs2670660 allele-specific GES are engaged in patients' peripheral blood mononuclear cells (PBMC) which encounter pathological conditions in coherent tissues of a human body during immune surveillance and homeostasis monitoring. These data indicate that expression of transRNAs encoded by specific intergenic sequences can trigger activation of innate immunity/inflammasome pathways and contribute to clinical development of autoinflammatory and autoimmune syndromes. Documented in this work single-base substitution-driven molecular and biological antagonisms of intergenic SNP-containing transRNAs suggest a guiding mechanism of selection and retention of phenotype-compatible intergenic variations during evolution. According to this model, random genetic variations which generate transRNAs asserting antagonistic phenotype-altering effects compared to ancestral alleles will be selected and retained as SNP variants.

Int J Neurosci. 2009; 119(9): 1261-1266
Ryan JJ, Glass LA, Bartels JM, Paolo AM

We extended the work of Rouleau et al. (I. Rouleau, D. P. Salmon, N. Butters, C. Kennedy, & K. McGuire, Quantitative and qualitative analyses of clock drawings in Alzheimer's and Huntington's disease. Brain and Cognition, 18, 1992, 70-87) and Ryan et al. (J. J. Ryan, S. J. Lopez, & S. W. Sumerall, Base rate of "10 to 11" clocks among patients referred for neuropsychological evaluation. Perceptual and Motor Skills, 81, 1995, 1138) by providing base rates for "10 to 11" clocks in samples of healthy elderly (n = 168), Alzheimer's disease (AD; n = 81), and Parkinson's disease (PD; n = 105). Groups were comparable in age and education. Stimulus bound clocks occurred in 3.0% of controls, 30.9% of AD, 5.7% of PD, and 10.2% of the combined sample. The 10.2% base rate is consistent with Ryan et al. for a mixed sample and Rouleau et al. for healthy elderly and patients with AD or Huntington's disease.

Mol Neurodegener. 2009 Nov 16; 4(1): 47
Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG

ABSTRACT: While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases.

Bioconjug Chem. 2009 Nov 16;
Viñas-Castells R, Holladay C, di Luca A, Díaz VM, Pandit A

Control of gene expression via small interfering RNA has enormous potential for the treatment of a variety of diseases, including cancer and Huntington's disease. However, before any therapies can be developed, effective techniques for controlled delivery of these molecules must be devised. In this proof-of-concept study, small interfering RNA was complexed with a polymer and loaded into a biomaterial scaffold. The scaffold was introduced primarily to control the release of the complexes, and the polymer was introduced to improve the transfection efficiency. An optimal dose and complexation ratio were selected, at which more than 50% down-regulation of the target gene Snail1 was observed in two-dimensional culture. Delayed release of the complexes was observed, and significant sustained down-regulation of Snail1 was seen in a three-dimensional scaffold system after 7 days. Thus, the use of the scaffold altered the transfection profile significantly, demonstrating the feasibility of a collagen scaffold as a controlled release system for delivery of small interfering RNA-dendrimer complexes.

J AOAC Int. 2009 Sep-Oct; 92(5): 1250-7
Teegala SM, Willett WC, Mozaffarian D

Consumption of industrially produced trans fatty acids (TFA) remains high in many populations, particularly in developing nations where partially hydrogenated vegetable oils are frequently used for home cooking and among individuals in developed countries having high intakes of bakery or processed foods. Well-controlled observational studies and randomized trials indicate that TFA consumption adversely affects multiple risk factors for chronic diseases, including numerous blood lipids and lipoproteins, systemic inflammation, endothelial dysfunction, and possibly insulin resistance, diabetes, and adiposity. Growing evidence for the latter effects is particularly concerning given the worldwide obesity pandemic and high contents of industrially produced TFA in many foods marketed toward children. Consistent evidence from prospective observational studies of habitual TFA consumption and retrospective observational studies using TFA biomarkers indicates that TFA consumption increases risk of clinical coronary heart disease (CHD). Based on the adverse effects of risk factors and consistent relationships with clinical endpoints, the evidence that TFA consumption increases CHD risk is convincing. Some evidence suggests that TFA consumption may also increase other disease outcomes, but further investigation is needed to confirm the presence and magnitude of such effects. More research is also needed to understand how specific TFA isomers of varying chain length and double bond location may affect different biologic pathways of disease. Both individual- and policy-level initiatives to decrease TFA consumption should continue, particularly in population subgroups and in developing nations with high consumption of partially hydrogenated vegetable oils.

J Clin Exp Neuropsychol. 2009 Nov 12; 1-9
van Walsem MR, Sundet K, Retterstøl L, Sundseth O

Previous studies investigating subclinical signs of cognitive decline in presymptomatic carriers of Huntington's disease (HD) have shown conflicting results. The current study examines cognition in 105 at-risk individuals, using a broad neuropsychological test battery and adopting strict inclusion criteria for attaining a homogeneous sample. Results obtained by analyses of variance and effect size calculations indicate no clinical evidence of significant cognitive decline in asymptomatic HD carriers very far from onset of illness compared to noncarriers. Closeness to disease onset amongst gene carriers influenced cognition negatively whereas cytosine-adenine-guanine (CAG) repeat size did not. The findings call for longitudinal follow-up studies using a combination of clinical instruments and experimental paradigms to pinpoint when subtle cognitive deficits occur and within which of the cognitive domains.

Rev Med Chil. 2009 Aug; 137(8): 1128-9
Pérez P C, Miranda C M, Segura-Aguilar J

Front Mol Neurosci. 2009; 2: 25
Baer K, Waldvogel HJ, Faull RL, Rees MI

Inhibitory neurotransmitter receptors for glycine (GlyR) are heteropentameric chloride ion channels that are comprised of four functional subunits, alpha1-3 and beta and that facilitate fast-response, inhibitory neurotransmission in the mammalian brain and spinal cord. We have investigated the distribution of GlyRs in the human forebrain, brainstem, and cervical spinal cord using immunohistochemistry at light and confocal laser scanning microscopy levels. This review will summarize the present knowledge on the GlyR distribution in the human brain using our established immunohistochemical techniques. The results of our immunohistochemical labeling studies demonstrated GlyR immunoreactivity (IR) throughout the human basal ganglia, substantia nigra, various pontine regions, rostral medulla oblongata and the cervical spinal cord present an intense and abundant punctate IR along the membranes of the neuronal soma and dendrites. This work is part of a systematic study of inhibitory neurotransmitter receptor distribution in the human CNS, and provides a basis for additional detailed physiological and pharmacological studies on the inter-relationship of GlyR, GABA(A)R and gephyrin in the human brain. This basic mapping exercise, we believe, will provide important baselines for the testing of future pharmacotherapies and drug regimes that modulate neuroinhibitory systems. These findings provide new information for understanding the complexity of glycinergic functions in the human brain, which will translate into the contribution of inhibitory mechanisms in paroxysmal disorders and neurodegenerative diseases such as Epilepsy, Huntington's and Parkinson's disease and Motor Neuron disease.

Nat Med. 2009 Nov 15;
Okamoto SI, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA

Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.

Nat Struct Mol Biol. 2009 Nov 15;
Tam S, Spiess C, Auyeung W, Joachimiak L, Chen B, Poirier MA, Frydman J

Aggregation of proteins containing polyglutamine (polyQ) expansions characterizes many neurodegenerative disorders, including Huntington's disease. Molecular chaperones modulate the aggregation and toxicity of the huntingtin (Htt) protein by an ill-defined mechanism. Here we determine how the chaperonin TRiC suppresses Htt aggregation. Unexpectedly, TRiC does not physically block the polyQ tract itself, but rather sequesters a short Htt sequence element, N-terminal to the polyQ tract, that promotes the amyloidogenic conformation. The residues of this element essential for rapid Htt aggregation are directly bound by TRiC. Our findings illustrate how molecular chaperones, which recognize hydrophobic determinants, can prevent aggregation of polar polyQ tracts associated with neurodegenerative diseases. The observation that short endogenous sequence elements can accelerate the switch of polyQ tracts to an amyloidogenic conformation provides a novel target for therapeutic strategies.

Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 10;
Gibrat C, Bousquet M, Saint-Pierre M, Lévesque D, Calon F, Rouillard C, Cicchetti F

Preclinical data suggest that cystamine stands as a promising neuroprotective agent against Huntington's and Parkinson's diseases. To decipher the mechanisms of action of cystamine, we investigated the effects of various doses of cystamine (10, 50, 200mg/kg) on the regulation of the brain-derived neurotrophic factor (BDNF), its receptor tropomyosin-receptor-kinase B (TrkB) and on the heat shock protein 70 (Hsp70) brain mRNA expression in relation to the time after administration. We have determined that the lower cystamine dose is the most efficient to promote putative neuroprotective effects. Indeed, an acute administration of 10mg/kg of cystamine increased the expression of BDNF mRNA in the substantia nigra compacta (SNc), although it did not significantly influence TrkB or Hsp70 mRNA. Higher cystamine doses resulted in the absence of activation of any of these markers or led to non-specific effects. We have also substantiated the neuroprotective effect of a 21-day treatment of 10mg/kg/day of cystamine in young adult mice against MPTP-induced loss of tyrosine hydroxylase-striatal fiber density, nigral dopamine cells and nigral Nurr1 mRNA expression. The neuroprotective action of cystamine in the same animals was associated with an upregulation of BDNF in the SNc. Taken together, these results strengthen the neuroprotective potential of cystamine in the treatment of Parkinson's disease and point towards the upregulation of BDNF as an important mechanism of action.

Exp Neurol. 2009 Nov 11;
Costa C, Tozzi A, Luchetti E, Siliquini S, Belcastro V, Tantucci M, Picconi B, Ientile R, Calabresi P, Pisani F

Since the anti-epileptic drug Zonisamide (ZNS) seems to exert beneficial effects in Parkinson's (PD) disease, we have investigated the electrophysiological effects of ZNS in a rat corticostriatal slice preparation. ZNS affected neither the resting membrane potential nor the input resistance of the putative striatal spiny neurons. In contrast, this drug depressed in a dose-dependent manner the current-evoked repetitive firing discharge with a EC(50) value of 16.38 muM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC(50) value of 32.5 muM. Reduced activity of the mitochondrial respiratory chain, particularly complex I and II, is implicated in the pathophysiology of PD and Huntington's (HD) diseases, respectively. Thus, ZNS was also tested in two different in vitro neurotoxic models obtained by acutely exposing corticostriatal slices either to rotenone, a selective inhibitor of mitochondrial complex I, or to 3-nitropropionic acid (3-NP), an inhibitor of complex II. Additionally, we also investigated the effect of ZNS in an in vitro model of brain ischemia. Interestingly, low concentrations of ZNS (0.3, 1, 3 and 10 muM) significantly reduced the rotenone-induced toxicity protecting striatal slices from the irreversible loss of corticostriatal field potential (FP) amplitude via a GABA-mediated mechanism. Conversely, this drug showed no protection against 3-NP and ischemia-induced toxicity. Our data indicate that relatively high doses of ZNS are required to decrease striatal neuronal excitability while low concentrations of this drug are sufficient to protect striatum against mitochondrial impairment suggesting its possible use in the therapy of basal ganglia neurodegenerative diseases.

Biochem Soc Trans. 2009 Dec; 37(Pt 6): 1270-5
Bithell A, Johnson R, Buckley NJ

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Biochem Soc Trans. 2009 Dec; 37(Pt 6): 1147-60
Hardingham GE

NMDA (N-methyl-D-aspartate) receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca(2+) influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischaemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington's disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render neurons vulnerable to secondary trauma. Thus responses to NMDA receptor activity follow a classical hormetic dose-response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death in response to both hyper- and hypo-activity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.

J Proteome Res. 2009 Nov 13;
Joyner PM, Matheke RM, Smith LM, Cichewicz RH

Metabolomics is a powerful multi-parameter tool for evaluating phenotypic traits associated with disease processes. We have used 1H NMR metabolome profiling to characterize metabolic aberrations in a yeast model of Huntington's disease that are attributable to the mutant huntingtin protein's gain-of-toxic-function effects. A group of 11 metabolites (alanine, acetate, galactose, glutamine, glycerol, histidine, proline, succinate, threonine, trehalose, and valine) exhibited significant concentration changes in yeast expressing the N-terminal fragment of a mutant human huntingtin gene. Correspondence analysis was used to compare results from our yeast model to data reported from transgenic mice expressing a mutant huntingtin gene fragment and Huntington's disease patients. This technique enabled us to identify a variety of both model specific (pertaining to a single species) and conserved (observed in multiple species) biomarkers related to mutant huntingtin's toxicity. Among the 59 metabolites identified, four compounds (alanine, glutamine, glycerol, and valine) changed significantly in concentration in all three Huntington's disease systems. We propose that alanine, glutamine, glycerol, and valine should be considered as promising biomarkers for evaluating new Huntington's disease therapies, as well as providing unique insight into the mechanisms associated with mutant huntingtin toxicity.

Mov Disord. 2009 Nov 11;
De Souza J, Jones LA, Rickards H

The aim of this study was to assess the criterion validity of three self-report measures of depression in a sample of patients with Huntington's disease (HD). Fifty patients with HD completed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Depression Intensity Scale Circles (DISCs). Current psychiatric status was assessed using the schedules for clinical assessment in neuropsychiatry (SCAN), and ICD-10 diagnosis was used as the gold standard. Receiver operating characteristics (ROC) curves were obtained and the sensitivity, specificity, positive, and negative predictive values were calculated for different cut-off scores on each rating scale. Twelve patients (24%) met ICD-10 criteria for depressive disorder. The depression sub-scale of the HADS (HADS-D) at an optimal cut-off of 6/7 was found to discriminate maximally between depressed and nondepressed patients in this population. The DISCs at a cut-off of 1/2 also performed well at detecting possible "cases" of depression, whereas the BDI-II performed the least satisfactorily of all scales. The HADS-D and DISCs are good screening measures for depression in the HD population and the DISCs may be particularly useful in those patients with more severe communicative and cognitive deficits. (c) 2009 Movement Disorder Society.

Ann N Y Acad Sci. 2009 Oct; 1180: 97-110
O'Keeffe GC, Michell AW, Barker RA

Parkinson's (PD) and Huntington's disease (HD) are chronic neurodegenerative conditions of the brain with a variety of clinical presentations including a disorder of movement and a range of nonmotor deficits. HD is genetic in origin and the causative gene and protein known, namely mutant Huntingtin, which leads to widespread early neuronal dysfunction and death throughout the brain. In contrast, the etiology of sporadic PD is unknown, and the pathology targets the nigrostriatal dopaminergic neurons with the formation of alpha-synuclein positive Lewy bodies. In both diseases, the ability to accurately diagnose the disease in the early stages and monitor progression over time remains a major challenge given the majority of the pathology is sited deep within the CNS. This challenge has gained extra significance as the development of disease-modifying drugs starts to emerge into the clinic. To this end, there is a need to find biomarkers that will help in the accurate diagnosis of the disease and/or prediction of its clinical onset as well as biomarkers that are able to faithfully track disease progression independent of any symptomatic effects of any therapies. In addition, these same markers may also help stratify each of these heterogeneous disorders into specific subtypes that share particular clinical and pathological characteristics.

Prion. 2009 Oct 16; 3(4):
Steele AD, Zhou Z, Jackson WS, Zhu C, Auluck P, Moskowitz MA, Chesselet MF, Lindquist S

Although it has been known for more than twenty years that an aberrant conformation of the prion protein (PrP) is the causative agent in prion diseases, the role of PrP in normal biology is undetermined. Numerous studies have suggested a protective function for PrP, including protection from ischemic and excitotoxic lesions and several apoptotic insults. On the other hand, many observations have suggested the contrary, linking changes in PrP localization or domain structure-independent of infectious prion conformation-to severe neuronal damage. Surprisingly, a recent report suggests that PrP is a receptor for toxic oligomeric species of a-beta, a pathogenic fragment of the amyloid precursor protein, and likely contributes to disease pathogenesis of Alzheimer's disease. We sought to access the role of PrP in diverse neurological disorders. First, we confirmed that PrP confers protection against ischemic damage using an acute stroke model, a well characterized association. After ischemic insult, PrP knockouts had dramatically increased infarct volumes and decreased behavioral performance compared to controls. To examine the potential of PrP's neuroprotective or neurotoxic properties in the context of other pathologies, we deleted PrP from several transgenic models of neurodegenerative disease. Deletion of PrP did not substantially alter the disease phenotypes of mouse models of Parkinson's disease or tauopathy. Deletion of PrP in one of two Huntington's disease models tested, R6/2, modestly slowed motor deterioration as measured on an accelerating rotarod but otherwise did not alter other major features of the disease. Finally, transgenic overexpression of PrP did not exacerbate the Huntington's motor phenotype. These results suggest that PrP has a context-dependent neuroprotective function and does not broadly contribute to the disease models tested herein.

J Histochem Cytochem. 2009 Nov 9;
Liao M, Chen X, Han J, Yang S, Peng T, Li H

Huntingtin-associated protein-1 (HAP1) was initially identified( )as a binding partner of huntingtin, the Huntington's disease( )protein. Based on its preferable distribution among neurons and endocrine cells, HAP1 has been suggested to play roles in vesicular transportation in neurons and hormonal secretion of endocrine cells. Given that HAP1 is selectively expressed in the islets of the rat pancreas, in this study, we analyzed the expressing pattern of HAP1 in the islets. In the rats injected intraperitoneally with streptozotocin that can selectively destroy the beta-cells of the pancreatic islets, the number of HAP1-immunoreactive cells was dramatically decreased, accompanied by a parallel decrease in number of insulin-immunoreactive cells. Immunofluorescent double staining of pancreas sections showed that, in the rat islets, HAP1 is selectively expressed in the insulin-immunoreactive beta-cells but not in the glucagon-immunoreactive alpha-cells and somatostatin-immunreactive delta-cells. In the isolated rat pancreatic islets, about 80% of cells expressed both HAP1 and insulin. Expression of HAP1 in the INS-1 rat insulinoma cell line was also demonstrated by immunofluorescent staining. Western blotting further revealed that HAP1 in both the isolated rat pancreatic islets and the INS-1 cells also has two isoforms, HAP1A and HAP1B, which are the same as those in the hypothalamus. These results demonstrated that HAP1 is selectively expressed in beta-cells of the rat pancreatic islets, suggesting that involvement of HAP1 in the regulation of cellular trafficking and secretion of insulin.