Candidate Review:

A Novel Pathophysiological Gene-Environment Interaction Suppresses the Neurotoxic Activities of (Mn) and Mutant HD

Gunnar F. Kwakye* and Aaron B. Bowman§

*Neuroscience Graduate Program, Vanderbilt University Medical School, U1205 Medical Center North, Nashville, TN 37232, USA.
§Department of Neurology, Vanderbilt University, Nashville, TN 37232, USA.
Correspondence to G.K. e-mail: gunnar.f.kwakye@vanderbilt.edu

Abstract | Full Text | PDF

ABSTRACT | Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration, emotional disturbance, and psychiatric disorder, which were first described by George Huntington in1872. Prevalence of HD is approximately 5 in 100,000 worldwide and 1 in 10,000 in the United States with a median age of onset at 391. Surprisingly, approximately 5% of patients have a juvenile form of the disease characterized by increased repeat length in comparison with adult HD onset. Unfortunately, there is currently no effective treatment for the disease. HD is caused by an expansion of a glutamine-encoding triplet repeat (CAG) in the huntingtin gene (IT15)1,2,3. Interestingly, both genetic and environmental factors have been reported to contribute to variability in age of disease onset. In fact, monozygotic twin4,5,6,7 and Venezuelan kindred studies8 have revealed significant environmental influences on the age of onset and clinical presentation of HD. The neuropathology of HD is characterized by selective degeneration of medium spiny neurons (MSNs) in the corpus striatum. The clinical presentation of HD reflects this selective vulnerability with patients exhibiting choreatic hyperkinetic movements. However, as the disease progresses, subsets of neurons within the cortex are lost, whereas the brainstem, cerebellum and hippocampus remain unaffected1. Several potential cellular mechanisms of HD neurotoxicity are supported by experimental evidence including alterations in iron homeostasis, energy metabolism, transcriptional regulation, brain-derived neurotophic factor (BDNF) signaling, axonal transport and altered calcium signaling9-14. A significant challenge in HD neuropathology is segregating the cellular pathologies into direct and indirect effects of HD neurotoxicity. This review will provide insights into studies that examine how metal ions modulate HD neuropathology. A discussion on wild-type huntingtin protein function and its relation to HD will commence the review, followed by environmental factors and aggregates in HD. The review will conclude with metal ion (manganese) essentiality and how its transport mechanisms may play a role in HD pathology.

HUNTINGTIN PROTEIN AND HD NEUROPATHOLOGY

The huntingtin gene encodes a large 350kDa protein called huntingtin, which when mutated in HD, causes progressive degeneration of the MSNs in the striatum. Huntingtin is a soluble cytoplasmic protein of 3,144 amino acids that is ubiquitously expressed in all regions of the brain and peripheral tissues14. The protein is enriched in neurons with similar expression patterns for wildtype and mutant huntingtin1. Despite its identification more than a decade ago, the function of wild-type huntingtin remains largely unclear. Huntingtin has many potential domains, boundaries and activities of which are not fully understood. One obviously significant portion of the mammalian protein is the polyglutamine (polyQ) region itself, which has been reported to be present in many transcription factors and aberrantly expanded in other disease-causing proteins16. Expansion of the polyQ tract alters the conformational state of the mutant protein and modifies fragmentation by proteolytic processing. Thus, the expanded polyQ tract is required for its subsequent aggregation and accumulation into inclusion bodies17-21. Although the relationship between polyQ aggregates and neurotoxicity is complex, recent data has demonstrated an inverse correlation between the polyQ protein inclusions neuropathology at the cellular level17,22-23. In unaffected individuals, the polyQ stretch in huntingtin begins at the eighteenth amino acid from the 5’ N-terminal region and contains up to 34 glutamine residues3. Data from Perutz et al in1994 showed that this region forms a polar zipper structure and suggested physiological interactions with other transcriptional factors that contain a polyQ region25. Bioinformatics analyses have reported 37 sequential HEAT repeat domains (named after similarity to domains found in the HD protein, Elongation factor 3, PR65/A subunit of protein phosphatase 2A, and TOR) spanning the entire protein, though other functional domains of the HD protein have also been identified26-30.The precise biological activity of HD is unknown, but many HEAT repeat containing proteins function as molecular scaffolds for stable interacting partners. While numerous interacting partners have been identified, the significance of these interactions to normal HD function is unclear. Huntingtin is found in multiple cellular compartments but localizes predominantly to the cytoplasm where it is found as both a soluble protein and in association with membranes including a variety of vesicles, organelles, and the plasma membrane. Subcellular localization may be important for HD pathogenesis, as nuclear localization of the mutant HD protein has been associated with increased neurotoxicity and correlates with neuropathology31,32. HD has been implicated in various cellular processes including iron metabolism, transcription, intracellular transport and membrane trafficking, axonal transport and mitochondrial function33,34. A major gap in our understanding of the disease mechanism is the absence of a known function for wild-type huntingtin. In 1995, three independent studies showed that the huntingtin gene is essential for normal embryonic development and neurogenesis: its complete inactivation in huntingtin-knockout mice results in embryonic lethality before day 8 (before gastrulation and the formation of the nervous system)35-37. Most intriguingly, the loss of huntingtin gene function in the adult brain results in motor dysfunction and a broad neurodegenerative phenotype, but not specifically for the neurons vulnerable to the polyglutamine-expanded disease protein37-39. The effects of polyglutamine expansion on HD function are unclear, although the mutant protein can rescue the embryonic lethal phenotype of the null mouse40. Evidence from mouse genetics and the dominant inheritance pattern of HD, indicates that HD is caused predominantly by a toxic gain-of-function, although there is also evidence for a dose-dependent neuroprotective loss-of-function. Thus, a pivotal question in HD research is aimed at understanding how mutant huntingtin causes selective neuronal pathology, especially in the MSNs of the striatum and pyramidal neurons in the motor cortex. One possibility is that environmental agents such as neurotoxic metal ions and toxins may modulate HD pathophysiology by promoting aberrant protein-protein interactions with mutant huntingtin to alter normal wild-type huntingtin physiological functions in striatal and cortical neurons. Thus, metal ions may facilitate mutant huntingtin’s toxic gain-of-function processes in HD neuropathology.

ENVIRONMENTAL FACTORS IN HD PATHOPHYSIOLOGY

Over a decade after the identification of the HD mutation, there has been conflicting reports linking complete or incomplete penetrance of HD to triplet repeat expansion length. Fortunately, Rubinsztein and other researchers have provided data which shows that triplet repeat expansion at the HD locus beyond 35 glutamine-encoding CAG repeats is sufficient to cause HD, though repeats between 36-40 show incomplete penetrance41,42. Although longer repeat length has been associated with earlier onset, repeat length in general account for only 60% of the variability in age of onset8. Thus, it is rationale to link both genetic and environmental factors as likely partners in contributing to HD, specifically, environmental factors contributing to the largest share of residual variability8,43. Gómez-Esteban and other researchers in the HD field have revealed significant environmental influences on the age of onset and clinical presentation in monozygotic twin studies that have the same number of expanded repeats45-48. Unfortunately, the aforementioned monozygotic twin studies failed to reveal the nature of the environmental factors involved. Animal models of HD have provided further support for the influence of environmental factors on HD onset and progression43,44. Indeed, Rozengzweig, Bennet and colleagues since the 1960s have studied the effects of environmental enrichment on the neuroanatomy and neurochemistry in wildtype animals that may enhance memory49. With these clear indications that environmental factors can influence HD pathophysiology, it is compelling to probe the possible contributing environmental factors and how they modulate HD pathophysiology.

THE ROLE OF METALS IN NEURODEGENERATIVE DISEASES

In the past decade, there has been a growing interest to understand the metabolism of neurotoxic metals and their influence on various neurodegenerative diseases, such as Manganism, Wilson’s, Parkinson’s, and Alzheimer’s diseases. Occupational and environmental exposures to these metals [Manganese (II) (Mn2+) and other metal ions (e.g. Cu2+, Zn2+, Al3+] have been suggested as a possible cause of neurodegenerative diseases. However, less attention has been focused on metals in HD neuropathology. Currently, there is evidence supporting amyloid fibrillogenesis and aggregation of proteins such as prion protein (PrP) and α-synuclein via Mn2+ and other metal ions (e.g. Cu, Al, Zn) interactions50. These proteins are metal ion binding proteins that interact with divalent metal ions to play a role in their altered conformational state, solubility, and aggregation51-56. However, in vitro analysis of prion protein aggregates have shown that Mn can promote aggregation independent of the PrP metal binding site55. Uversky has proposed that polyvalent metal ions, such as Mn, may promote aggregation by cross-linking protein carboxylates56. Comparatively, Perutz and Green have also hypothesized that the mechanisms of neuronal intranuclear inclusions (NIIs) of mutant huntingtin (aggregates) in HD is either via polar zipper formation or covalent bonding by transglutaminase-catalyzed cross-linking24,57. Given the strong association between protein aggregation, metal ions and neurodegeneration, it is highly rationale to speculate that metal ions have the potential to modulate HD pathophysiology.

RELATIONSHIP BETWEEN ALTERED METAL ION HOMEOSTASIS, METAL TOXICITY, AND HD

The clinical progression of HD has been reported to be associated with altered metal ion homeostasis, wherein iron and copper are significantly elevated in the corpus striatum58. In addition, data from animal models have also shown that there is significant increase in the levels of microglia ferritin, an intracellular iron storage protein 59. In fact, a common phenomenon in multiple neurodegenerative diseases is the alteration of various metal ion levels, and their obvious neurotoxic consequences. Although the distribution of metals throughout the brain is not uniform, metal ion accumulation in specific brain regions reflects neurotoxicity (example: manganese accumulation and neurotoxicity in the globus pallidus results in manganism). Interestingly, Fox et al have recently reported that huntingtin protein interacts with Cu ions, with this specific metal binding decreasing the solubility of wild-type huntingtin protein60. However, the cellular effects of Cu or other metal ions on HD function, proteolytic processing to generate N-terminal fragments, aggregation of fragments, and formation of mutant huntingtin inclusion bodies remain unknown. A recent study suggested that inclusion bodies formed by CAG expansion in mutant huntingtin protein fragments are associated with iron-dependent oxidative events, opening the possibility that other redox-reactive metal ions, such as Mn, may influence polyglutamine aggregation61. In essence, several studies have provided evidence that supports a role for oxidative stress, mitochondrial dysfunction, excitotoxicity, and alterations in iron homeostasis as critical steps in both Mn neurotoxicity and HD neuropathology. Importantly, chronic exposure of Mn in animal models shows significant accumulation in the striatum, providing any potential interaction between Mn and HD to occur within the neurons most vulnerable to HD pathology. Unfortunately, there are currently no reported studies examining the connection between metal exposure, including Mn and HD neuropathology. With the increasing evidence supporting strong association between metal ions and protein aggregation, similarities between metal ion cytotoxicity and cellular pathways of neurodegeneration, altered metal ion homeostasis, and the differential accumulation of various metals across neuronal subtypes, it is highly rationale to propose that metal ions with neurotoxic properties are the strongest candidates for the largest residual environmental variability that has been hypothesized to modulate selective neurodegenerative process in HD. In an attempt to identify the link between HD and metal ions, our lab has screened the impact of several neurotoxic metal ions on a striatal cell line model of HD and found striking interactions between mutant huntingtin expression and Mn exposure, wherein mutant huntingtin protein and Mn suppress the neurotoxic activities of each other. The remaining sections of this review will focus on manganese essentiality, neurotoxicity, mechanisms of transport and its possible link to HD.

MANGANESE: ESSENTIALITY AND NEUROTOXICITY

Mn is an essential ubiquitous trace element required for normal growth, development and functioning in all bodily tissues, and cellular homeostasis62. In humans and animals, manganese functions as a cofactor for several Mn-dependent enzymes that are appropriate for neuron or glial cell function, as well as enzymes involved in neurotransmitter synthesis and metabolism. These Mn-dependent enzymes include glutamine synthetase, pyruvate decarboxylase, superoxide dismutase 2 (SOD2), and arginase63. The idea of Mn involvement in HD stems from earlier studies by Butterworth in 1986 where it was shown that there are significant decreases in Mn-dependent enzymes, specifically, glutamine synthetase and pyruvate carboxylase in the caudate nucleus of HD patients64. Interestingly, given Mn essentiality, inadequate intake of Mn can result in abnormal glucose tolerance65. Despite its essentiality in multiple metabolic functions, Mn can be toxic at high concentrations. The brain in particular is highly susceptible to Mn neurotoxicity. Excessive dietary intake and environmental exposures to Mn for longer periods result in accumulation of Mn in the globus pallidus, striatum and subthalamic nucleus of the basal ganglia, which causes a clinical disorder referred to as manganism. This disorder causes extrapyramidal symptoms that resemble idiopathic Parkinson’s disease (IPD). Although extensive studies have been conducted to link altered manganese levels to IPD, the connection between manganese and HD remain unknown. Mn exposure and increased brain Mn levels may modulate other neurodegenerative diseases (example: Alzheimer’s and polyglutamine diseases) in which protein aggregation and amyloid deposition are parts of the pathophysiology. Recent data shows that non-human primates exposed to Mn have diffuse amyloid-Beta plaques in the frontal cortex, similar to what is seen in Alzheimer’s patients66. This is particularly interesting in light of the observation that Mn levels are elevated in Alzheimer disease brains67. Indeed alterations in various brain metals, including Mn, have been suggested to modulate sensitivity to oxidative stress, which likely plays a fundamental role in the pathophysiology of most neurodegenerative disease states. For example, a possible mechanism by which Mn exposure may modulate neurodegenerative conditions is through alterations in Mn-dependent antioxidant enzyme SOD2 level or activity. It is known that reduction of SOD2 levels enhances Alzheimer’s disease pathology in a transgenic mouse model68. Preferentially enhanced NMDA (N-methyl-D-aspartic acid) receptor mediated excitotoxicity, mitochondrial dysfunction, and oxidative stress have also been implicated in HD1,69. Exposure of rats to Mn was found to decrease the levels of two manganese bound enzymes, SOD2 and glutamine synthetase, in the basal ganglia70. Furthermore, recent data from HD mouse models have also linked altered arginase activity resulting in urea cycle deficiency71. Thus, Mn exposure may diminish the activities of Mn-dependent enzymes, thereby contributing to the HD pathophysiology.

MECHANISMS OF MANGANESE TRANSPORT

Unpublished data from our lab shows that mutant HD striatal cell cultures are resistant to Mn toxicity relative to wild-type, over a broad Mn concentration range. This observation suggests a strong interaction between mutant huntingtin and Mn. It is highly rationale to speculate perturbations in Mn transport (import and export) and storage in the aforementioned mutant striatal cell line models of HD. The remainder of this review will focus on the mechanisms of manganese transport. Due to the delicate relationship between Mn’s essentiality and toxicity, both the absorption and tissue levels of this metal are tightly regulated. Mn can cross the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB) on several carrier(s) and in different oxidation states72,73. Unfortunately, no unique mammalian Mn transporter has yet been identified. It appears that several potential modes of Mn transport across the BBB and BCB have been reported and others speculated to occur via facilitated diffusion, active transport, divalent metal transporter 1 (DMT-1)-mediated transport, voltage-regulated and stored operated Ca2+ channels, ZIP8, citrate, and transferrin (Tf)- dependent transporters72. Of all the above listed polyvalent transporters, Tf and DMT1 are the most extensively documented74. Approximately 80% of Mn in plasma is bound to beta1-globulin and albumin and a smaller fraction of Mn is bound to transferrin (Tf), an iron-binding protein75. Mn binding to Tf is time-dependent and Tf receptors have been shown to be present on cerebral capillary surfaces74. When complexed with Tf for transport across the BBB, Mn is exclusively present in the trivalent oxidation-state76. Another critical regulator of brain Mn levels is the divalent metal transporter (DMT-1). The transporter belongs to the family of natural resistance-associated macrophage protein (NRAMP) and has also been referred to as the divalent cation transporter (DCT). Gene transcription of this protein is regulated by Fe concentration via a Fe-response element (IRE) located on the mRNA77. Orthologous mutations (glycine 185 to arginine) in the DMT-1 gene of the Belgrade (b) rat, and microcytic anemia (mk) mouse result in significantly lower Mn and Fe tissue levels, including the brain78,79. The reduction in brain Mn and Fe uptake in the above animal models suggests that defective DMT-1 allele alters the disposition of both metals and that Mn and Fe may utilize DMT-1 as a putative transporter across the BBB and BCB. These results support the notion that impaired DMT1 alters Mn transport due to a defect in Mn uptake, export and storage.

Given the above evidence of metal ions (example, Mn) essentiality and neurotoxicity in neurodegenerative diseases, specifically HD, and alterations in Mn transport and levels in HD animal models, it is highly likely that there exists a gene-environment interaction between mutant huntingtin and Mn that may modulate HD pathophysiology. However, the identification and functional characterization of both Mn transport pathways and Mn-bound proteins is not completely understood. Thus, further investigations would have to be conducted to support the gene-environment interaction hypothesis between mutant huntingtin and Mn in HD neuropathology.

REFERENCES

1.       Cowan CM, et al (2006). Selective neuronal degeneration in Huntington's disease. Curr Top Dev Biol. 75: 25-71.

2.       Bates G (2005). History of genetic disease: the molecular genetics of Huntington disease - a history. Nature Reviews Genetics. 6: 766-773.

3.       Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeats that is expanded and unstable on Huntington’s disease chromosomes. Cell. 72: 971-983.

4.       Anca MH, et al (2004). Different phenotypic expression in monozygotic twins with Huntington disease. Am J Med Genet A. 124: 89-91.

5.       Friedman JH, Trieschmann ME, Myers RH and Fernandez HH (2005). Monozygotic twins discordant for Huntington disease after 7 years. Arch Neurol. 62: 995-7.

6.       Georgiou N, et al (1999). Differential clinical and motor control function in a pair of monozygotic twins with Huntington's disease. Mov Disord. 14: 320-5.

7.       Gomez-Esteban JC, et al (2007). Monozygotic twins suffering from Huntington's disease show different cognitive and behavioural symptoms. Eur Neurol. 57: 26-30.

8.       Wexler NS, et al (2004). Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl Acad Sci USA. 101: 3498-3503.

9.       Borrell-Pages M, Zala D, Humbert S and Saudou F (2006). Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci. 63: 2642-60.

10.    Browne SE and Beal MF (2004). The energetics of Huntington's disease. Neurochem Res. 29: 531-46.

11.    Gatchel JR and Zoghbi HY (2005). Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 6: 743-55.

12.    Ross CA (2002). Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron. 35: 819-22.

13.    Sugars KL and Rubinsztein DC (2003). Transcriptional abnormalities in Huntington disease. Trends Genet. 19: 233-8.

14.    Zhang H, et al (2008). Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington’s disease. Neurobiol Dis. 31: 80-88.

15.    Cattaneo E, et al (2001). Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci. 24: 182-188.

16.    Everett CM and Wood NW (2004). Trinucleotide repeats and neurodegerative diseases. Brain. 127: 2385-2405.

17.    Ross CA and Poirier MA (2004). Protein aggregation and neurodegenerative disease. Nat Med. 10 (Suppl): S10-7.

18.    Ross CA, et al (2003). Polyglutamine fibrillogenesis: the pathway unfolds. Proc Natl Acad Sci U S A. 100: 1-3.

19.    Michalik A and Van Broeckhoven C (2003). Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet. 12 (Spec No 2): R173-86.

20.    Persichetti F, et al (1999). Mutant huntingtin forms in vivo complexes with distinct context-dependent conformations of the polyglutamine segment. Neurobiol Dis. 6: 364-75.

21.    Schaffar G, et al (2004). Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell. 15: 95-105.

22.    Arrasate M, et al (2004). Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 431: 805-10.

23.    Bowman AB, et al (2005). Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet. 14: 679-91.

24.    Perutz MF, et al (1994). Glutamine repeats as polar zippers: their possible role in the inherited neurodegenerative diseases. Proc. Natl Acad. Sci. USA. 91: 5355-5358.

25.    Rockabrand E (2007). The first 17 amino acids of Huntingtin modulate its subcelular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet. 16: 61-77.

26.    Takano H and Gusella JF (2002). The predominantly HEAT-like motif structure of Huntingtin and its association and coincident nuclear entry. BMC Neurosci. 3: 15.

27.    Xia J, et al (2003). Huntingtin contains a conserved nuclear export signal. Hum Mol Genet. 12: 1393-1403.

28.    DiFiglia M, et al (1997).  Aggregation of neuronal intranuclear inclusions and dystrophic neuritis in brain. Science. 277: 1990-1993.

29.    Wellington CL, et al (2004). Inhibiting caspase cleavage of huntingtin   reduces toxicity and aggregation formation in neuronal and nonneuronal cells. J.Biol.Chem. 275: 19831-19838.

30.    Warby SC, et al (2005). Huntington phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum Mol Genet. 14: 1569-1577.

31.    Atwal RS, et al (2007). Huntingtin Has a Membrane Association Signal that Can Modulate Huntingtin Aggregation, Nuclear Entry and Toxicity. Hum Mol Genet. 16 (21): 2600-15.

32.    Van Raamsdonk JM, et al (2005). Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Hum Mol Genet. 14: 3823-35.

33.    Cattaneo E et al (2005). Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci. 6: 919-30.

34.    Zhang Y, et al (2006). Huntingtin inhibits caspase-3 activation. Embo J. 25: 5896-906.

35.    Nasir J, et al (1995). Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 81: 811-23.

36.    Duyao MP, et al (1995). Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science. 269: 407-410.

37.    Zeitlin S, et al (1995). Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nature Genet. 11: 155-163.

38.    Dragatsis I, et al (2000). Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet. 26: 300-6.

39.    Van Raamsdonk JM, et al (2005). Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease. Hum Mol Genet. 14: 1379-1392.

40.    White JK, et al (1997). Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet. 17: 404-10.

41.    McNeil SM, et al (1997). Reduced penetrance of the Huntington's disease mutation. Hum Mol Genet. 6: 775-9.

42.    Rubinsztein DC, et al (1996). Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 59: 16-22.

43.    Van Dellen A, et al (2005). Gene-environment interactions, neuronal dysfunction and pathological plasticity in Huntington's disease. J. Clin Exp Pharmacol Physiol. 32: 1007-19.

44.    Garcia M, et al (2002). The Mitochondrial Toxin 3-Nitropropionic Acid Induce Striatal Neurodegeneration via a c-Jun N-terminal Kinase/c-Jun Module.  J. Neurosci. 22: 2174-2184.

45.    Gomez-Esteban JC, et al (2007). Monozygotic twins suffering from Huntington's disease show different cognitive and behavioural symptoms. Eur Neurol. 57: 26-30.

46.    Anca MH, et al (2004). Different phenotypic expression in monozygotic twins with Huntington disease. Am J Med Genet A. 124: 89-91.

47.    Friedman JH, et al (2005). Monozygotic twins discordant for Huntington disease after 7 years. Arch Neurol. 62: 995-7.

48.    Georgiou N, et al (1999). Differential clinical and motor control function in a pair of monozygotic twins with Huntington's disease. Mov Disord. 14: 320-5.

49.    Bennett DA, et al (1964). Chemical and anatomical plasticity of brain. Science. 146: 610-619.

50.    Gaeta A and Hider RC (2005). The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy. Br J Pharmacol. 146: 1041-59.

51.    Binolfi A, et al (2006). Interaction of alpha-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement. J Am Chem Soc. 128: 9893-901.

52.    Giese A, et al (2004). Effect of metal ions on de novo aggregation of full-length prion protein. Biochem Biophys Res Commun. 320: 1240-6.

53.    Jobling MF, et al (2001). Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126. Biochemistry. 40: 8073-84.

54.    Levin J, et al (2005). Single particle analysis of manganese-induced prion protein aggregates. Biochem Biophys Res Commun. 329: 1200-7.

55.    Tsenkova RN, et al (2004). Prion protein fate governed by metal binding. Biochem Biophys Res Commun. 325: 1005-12.

56.    Uversky VN, et al (2001). Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure. J Biol Chem. 276: 44284-96.

57.    Green H (1993). Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell. 74: 955-956.

58.    Dexter DT, et al (1991). Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain. 114 (Pt 4) : 1953-75.

59.    Simmons DA, et al (2007). Ferritin Accumulation in Dystrophic Microglia is an Early Event in the Development of Huntington’s Disease. Glia. 55: 1074-1084.

60.    Fox JH, et al (2007). Mechanisms of Copper Ion Mediated Huntington’s Disease Progression. PLoS ONE 2: e334.

61.    Firdaus WJ, et al (2006). Huntingtin inclusion bodies are iron-dependent centers of oxidative events. Febs J. 273: 5428-41.

62.    Eriksson K, et al (2005). Interactions between excessive exposures and dietary iron-deficiency in neurodegeneration. Environ.Toxicol.Pharmacol. 19: 415-42.

63.    Eriksson K and Aschner M (2003). Manganese neurotoxicity and glutamate-GABA interaction. Neurochem. Int. 43: 475-480.

64.    Butterworth J (1986). Changes in Nine Enzyme Markers for Neurons, Glia, and Endothelial Cells in Agonal State and Huntington’s Disease Caudate Nucleus.  J. Neurochem. 47: 583-587.

65.    Freeland-Graves JH, et al (1994). Models to study manganese deficiency, Manganese in Health and Disease. (Klimis-Travantzis DJ, Ed): p. CRC Press, Boca Raton, FL.

66.    Guilarte TR, et al (2008). Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. J Neurochem. 105: 1948-1959.

67.    Maynard CJ, et al (2005). Metals and amyloid-beta in Alzheimer's disease. Int J Exp Pathol. 86: 147-159.

68.    Esposito L, et al (2006). Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci. 26: 5167-5179.

69.    Shehadeh J, et al (2006). Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiol of Disease. 26: 392-403.

70.    Morello M, et al (2007). Manganese intoxication decreases the expression of manganoproteins in the rat basal ganglia: an immunohistochemical study. Brain Res Bull. 74: 406-415.

71.    Chiang M, et al (2007). Dysregulation of C/EBPalpha by mutant huntingtin causes the urea cycle deficiency in Huntington’s disease. Hum Mol Genet. 16: 483-498.

72.    Aschner M, et al (2007). Manganese: Recent advances in understanding its transport and neurotoxicity. Toxicology and Pharmacology. 21: 131-147.

73.    Wang X, et al (2008). Intracellular localization and subsequent redistribution of metal transporters in a rat choroids plexus model following exposure to manganese or iron. Toxicol and App. Pharmacol. 230: 167-174.

74.    Aschner M and Gannon M (1994). Manganese (Mn) transport across the rat blood-brain barrier: saturable and transferrin-dependent transport mechanisms. Brain Res Bull. 33: 345-349.

75.    Foradori AC, et al (1967). The discrimination between magnesium and manganese by serum proteins. J Gen Physiol. 50: 2255-2266.

76.    Aisen P, et al (1969). The chromium, manganese, and cobalt complexes of transferrin. J Biol Chem, 244: 4628-4633.

77.    Garrick MD, et al (2003). DMT1: a mammalian transporter for multiple metals. Biometals. 16: 41-54.

78.    Fleming MD, et al (1998). Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci. 95: 1148-1153.

79.    Fleming MD, et al (1997). Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 16: 383-386.

FURTHER INFORMATION

Aaron Bowman’s Lab