The expression of the Drosophila huntingtin transcript was examined at different developmental stages by using Northern blot analysis. A transcript of the predicted size, ~12 kb in length, was detected in all embryonic stages examined, in third-instar larvae and in adults. A second, fainter band of ~5 kb was also observed when a 5' riboprobe was used to probe the blot, but not when riboprobes from other regions of Drosophila HD were used. The transcript is expressed widely, which is similar to the case in mammalian HD genes. A hybridization signal was detected only in poly(A)+ fractions and not in total RNA from Drosophila tissues. The Drosophila huntingtin transcript is present at very low levels, consistent with the results of embryonic cDNA library screens where only three partial length positive clones were found among 3×106 plaques screened (Li, 1999).
Drosophila larvae with mutations in genes encoding axonal transport proteins show dramatic neuromuscular pathology. Segmental nerves of such mutant animals contain prominently stained accumulations of synaptic vesicle proteins such as synaptotagmin (SYT) and cysteine string protein (CSP) (Hurd, 1996; Bowman, 1999). Recently, deletants of the Drosophila APPL gene (which is proposed to function as a vesicular receptor for kinesin-I) were found to exhibit phenotypes characteristic of axonal transport defects (Gunawardena, 2001). To test if reduction of Drosophila huntingtin (htt) causes axonal transport phenotypes, tissue-specific reduction of Drosophila htt was generated by using a modified RNAi method. Three independent UAS double-strand htt hairpin RNAi transgenic lines (dhtt#1, #9, and #13) were combined with the neuronal APPL-GAL4 driver. Expression of htt RNA in the dhtt-RNAi lines was observed by RT-PCR to be reduced, in some instances to as little as 10%-30% of normal. All three lines exhibited defects characteristic of axonal transport problems (organelles accumulate within larval nerves) as well as a small amount of neuronal cell death in the larval brain. As controls, UAS double-strand RNAi lines of RhoGAP were combined with APPL-GAL4. These combinations did not cause axonal transport defects, although disruption of RhoGAP in the adult eye using GMR-GAL4 or eyeless-GAL4 caused a rough eye phenotype (Gunawardena, 2003).
Ordinarily, deleting one of two copies of motor genes does not produce a significant phenotype, but such a reduction combined with a reduction of a putative cargo binding partner is predicted to enhance an axonal transport phenotype because of the additional reduction in components required for transport. To test this prediction, larvae were generated that had reduced levels of both htt and motor proteins. Axonal blockages in the presence of reduced htt gene function were enhanced by a 50% reduction in kinesin heavy chain (KHC) or kinesin light chain (KLC) gene dosage; a small enhancement of neuronal cell death was also observed. A 50% reduction of dynein heavy chain (DHC) or dynein light chain gene (DLC) dose did not dramatically increase the amount of organelle accumulations or the amount of neuronal cell death (Gunawardena, 2003).
Since adults and pupae mutant for DLC, dynein intermediate chain, and the dominant-negative mutation p150Glued have rough eye phenotypes, it was asked if loss or disruption of htt would also exhibit this phenotype. Reduction of htt in the eye using the GMR-GAL4 driver caused a rough eye phenotype in adults; this is also characteristic of neurodegeneration. This phenotype was progressive over time (10 days), causing severe problems of morphology and pigmentation, leading to patches of dark areas indicative of death. Sections of aged mutant eyes showed loss of cells beneath the external surface of the eye and disruption in the normal ommatidial morphology, suggesting loss of photoreceptor integrity. These results suggest that htt has a function in the axonal transport machinery and that loss of htt can lead to neurodegeneration (Gunawardena, 2003).
The observation that reduction of htt causes an axonal transport phenotype, combined with previous work linking htt to the transport machinery, led to the hypothesis that excess htt, particularly htt containing pathogenic polyQ repeats, should cause axonal blockages by titrating motor proteins away from other cargo. To test this proposal, human huntingtin exon 1 was expressed with either a 'normal' length of polyQ (httex1-20Q) or with a disease-causing length of polyQ (httex1-93Q; Steffan, 2001) in larval neurons. These transgenic lines were crossed to two neuron-specific GAL4 driver lines, APPL-GAL4 and 179Y-GAL4, and their nerves were stained for synaptic vesicle markers. While httex1-20Q nerves were similar to wild-type, two different httex1-93Q lines had organelle accumulations characteristic of defects in axonal transport (Gunawardena, 2003).
If expression of httex1 with pathogenic polyQ repeats causes axonal transport phenotypes by titrating motor proteins from other cargoes and pathways, then reduction of motor protein gene dosage in larvae overexpressing httex1 is predicted to significantly enhance the axonal transport phenotype by further reducing the available motor protein pool. To test this prediction, larvae were generated that overexpressed httex1-20Q or httex1-93Q and were heterozygous for motor protein gene mutations. A 50% reduction in KHC or DLC with httex1-93Q enhanced the amount of organelle accumulations, while KHC or DLC reductions combined with httex1-20Q were comparable to wild-type (Gunawardena, 2003).
TUNEL analysis was used to test whether perturbations caused by httex1 causes neuronal apoptosis. While the transgenic line expressing httex1-20Q was comparable to wild-type, the transgenic lines expressing httex1-93Q showed some neuronal apoptosis; a strong enhancement of neuronal death was also observed with 50% reduction in KHC and a small increase with 50% reduction in DLC (Gunawardena, 2003).
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of a translated CAG repeat in the N terminus of the huntingtin (htt) protein. This study describes the generation and characterization of a full-length HD Drosophila model to reveal a previously unknown disease mechanism that occurs early in the course of pathogenesis, before expanded htt is imported into the nucleus in detectable amounts. Expression of expanded full-length mammalian htt (128QhttFL) in Drosophila leads to behavioral, neurodegenerative, and electrophysiological phenotypes. These phenotypes are caused by a Ca2+-dependent increase in neurotransmitter release efficiency in 128QhttFL animals. Partial loss of function in synaptic transmission (syntaxin, Snap, Rop) and voltage-gated Ca2+ channel genes suppresses both the electrophysiological and the neurodegenerative phenotypes. Thus, the data indicate that increased neurotransmission is at the root of neuronal degeneration caused by expanded full-length htt during early stages of pathogenesis (Romero, 2008).
Expression of 128QhttFL in the eye using GMR-GAL4 leads to progressive photoreceptor neuron degeneration. Histological examination of the internal eye structure in flies of different ages reveals that the number and arrangement of rhabdomeres in photoreceptor cells is relatively normal in 1-day-old flies, but degeneration is evident at day 20. Expression of 128QhttFL in motor neurons leads to motor impairment phenotypes. The 128QhttFL animals perform as controls do in a climbing assay when they are young, but their motor performance declines prematurely as they age. Moreover, flying ability is impaired in aged 128QhttFL flies, and they also show progressive loss of NMJs at the IFM. In addition, these flies show a reduced survival rate when compared with controls (Romero, 2008).
These neurodegenerative phenotypes are not likely a consequence of transcriptional dysregulation, because they occur in the absence of obvious nuclear htt, even in aged flies. The possibility was investigated that axonal blockages trigger the phenotypes observed in 128QhttFL flies; axonal blockages and impaired fast axonal transport have been reported following expression of polyglutamine tracts alone or in the context of other polypeptides, including expanded htt. However, this study did not detect htt or synaptotagmin accumulation in the axons of 128QhttFL flies, even though the observation of axonal blockages reported with an expanded htt fragment was reproduced. Despite the absence of visible htt or synaptotagmin aggregates, the possibility that intracellular transport is decreased cannot be excluded. However, mislocalization or aberrant distribution of known synaptic markers that rely on vesicular transport for their proper synaptic localization was not observed (Romero, 2008).
All together, these data suggest that the presynaptic accumulation of 128QhttFL impairs the function of factors involved in neurotransmitter release. This hypothesis agrees with abundant data describing protein interactions between htt and components of the synaptic machinery (Smith, 2005) and with findings in R6/1 and R6/2 mouse models that suggested a role for altered neurotransmitter release as a potential mechanism of HD pathogenesis. In R6/2 mice, synapsin phosphorylation is partially defective (Lievens, 2002), and in R6/1 mice glutamate levels are reduced and aspartate and GABA are increased (Nicniocaill, 2001). Moreover, increased NMDA receptor activity has been reported in full-length HD mice (Cepeda, 2001, Zeron, 2002), leading to a postsynaptic increase in Ca2+ influx and abnormal synaptic transmission. In addition, Ca2+ levels were found to be increased by almost 2-fold in CA1 pyramidal neurons in full-length HD mice (Hodgson, 1999). However, no defects were observed in paired-pulse facilitation, which questions the biological relevance of this finding. In addition, mutant htt has been implicated in aberrant mitochondrial Ca2+ buffering (Panov, 2005), and it also increases the sensitivity of the inositol 1,4,5-triphosphate (IP3) receptor to IP3, causing enhanced Ca2+ release following mGluR1/5 activation (Tang, 2003). These data suggest that cytosolic Ca2+ levels play a role in HD pathogenesis (Bezprozvanny, 2004; Romero, 2008 and references therein).
To test whether expanded htt impairs the normal function of proteins involved in synaptic transmission, a genetic approach was used, using the 128QhttFL animals. This study found that partial loss of function of Snap, syntaxin, or Rop restores the increased EJP amplitude observed in 128QhttFL larvae to near-normal levels. Moreover, the lack of neurotransmitter release failures is also suppressed by these mutations. These observations suggest that neurodegeneration in 128QhttFL flies is caused by increased synaptic transmission. In agreement with this hypothesis, a progressive neurodegenerative phenotype was found in the NMJ of adult 128QhttFL animals. Most importantly, further support for this hypothesis comes from the observation that the same synaptic transmission mutants that restore the EJP amplitude and release failure abnormalities also suppress motor impairment, photoreceptor degeneration, or both in 128QhttFL adult animals (Romero, 2008).
Ca2+ levels have a bimodal distribution in 128QhttFL flies, with some boutons showing high Ca2+ levels and other boutons within the same neuromuscular junction showing levels in the normal range. This distribution can be correlated with the accumulation pattern of htt, which is present in some boutons and absent in others within a given neuromuscular junction. The hypothesis was tested that Ca2+ levels are relevant for the increased transmission and decreased failures observed in 128QhttFL animals using mutations in voltage-gated Ca2+ channels. It was found that Ca2+ levels are restored within normal range in 128QhttFL flies carrying heterozygous mutations in either Syx or the Dmca1D Ca2+ channel. Furthermore, heterozygous mutants for either the Dmca1A or Dmca1D Ca2+ channels also show suppression of the increased transmission and decreased failure phenotypes. Dmca1D, an L-type voltage-gated Ca2+ channel, was also tested in the context of the eye assay and found that its partial loss of function suppresses photoreceptor degeneration. These data support the hypothesis that increased Ca2+ levels play an important role in the observed increased transmission in neurons of 128QhttFL animals. Interestingly, mutations in K+ channels cause neurodegeneration in flies and in humans, further supporting the idea that the increased release is responsible, at least in part, for neuronal degeneration caused by expanded htt (Romero, 2008).
The findings described in this report unveil a mechanism of pathogenesis for expanded htt that does not require its nuclear accumulation in detectable amounts. The increased synaptic transmission phenotype exerted by full-length htt likely represents a mechanism of pathogenesis taking place at early stages of disease progression. In later stages, cleavage of htt would compound the toxic effects of the full-length protein with fast axonal transport impairments and transcriptional dysregulation caused by N-terminal fragments. These findings point to increased synaptic transmission as a therapeutic target with the potential of delaying HD onset and thus likely impacting disease progression. The genetic data showing suppression of the synaptic transmission and neurodegenerative phenotypes further define specific therapeutic targets and support the idea that Ca2+ channel antagonists, and perhaps other inhibitors of neurotransmission, offer an attractive therapeutic option due to their specificity and wide usage (Romero, 2008).
Reference names in red indicate recommended papers.
Andrade, M. A. and Bork, P. (1995). HEAT repeats in the Huntington's disease protein. Nat. Genet. 11: 115-116. 7550332
Andrade, M. A., et al. (2001). Comparison of ARM and HEAT protein repeats. J. Mol. Biol. 309: 1-18. 11491282
Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. and Bonini, N. M. (2002). Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295: 865-868. 11823645
Becher, M. W., Kotzuk, J. A., Sharp, A. H., Davies, S. W., Bates, G. P., Price, D. L., and Ross, C. A. (1998). Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4: 387-397. 9666478
Bezprozvanny, I., and Hayden, M. R. (2004). Deranged neuronal calcium signaling and Huntington disease. Biochem. Biophys. Res. Commun. 322: 1310-1317. PubMed citation: 15336977
Block-Galarza, J., Chase, K. O., Sapp, E., Vaughn, K. T., Vallee, R. B., DiFiglia, M. and Aronin, N. (1997). Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport 8: 2247-2251. 9243620
Bonini, N.M. (2002). Chaperoning brain degeneration. Proc. Natl. Acad. Sci. 99: (Suppl 4) 16407-16411. 12149445
Bowman, A. B., Patel-King, R. S., Benashski, E., McCaffery, J. M., Goldstein, L. S. and King, S. M. (1999). Drosophila roadblock and Chlamydomonas LC7: a conserved family of dynein-associated proteins involved in axonal transport, flagellar motility, and mitosis. J. Cell Biol. 146: 165-180. 10402468
Bowman, A. B., Kamal, A., Ritchings, B. W., Philp, A. V., McGrail, M., Gindhart, J. G. and Goldstein, L. S. (2000). Kinesin-dependent axonal transport is mediated by the sunday driver (SYD) protein. Cell 103: 583-594. 11106729
Boylan, K., Serr, M. and Hays, T. (2000). A molecular genetic analysis of the interaction between the cytoplasmic dynein intermediate chain and the glued (dynactin) complex. Mol. Biol. Cell 11: 3791-3803. 11071907
Busch, A., et al. (2003). Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington's disease. J. Biol. Chem. 278(42): 41452-61. 12888569
Cattaneo, E., Rigamonti, D., Goffredo, D., Zuccato, C., Squitieri, F. and Sipione, S. (2001). Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci. 24: 182-188. 11182459
Cepeda, C., Ariano, M. A., Calvert, C. R., Flores-Hernandez, J., Chandler, S. H., Leavitt, B. R., Hayden, M. R. and Levine, M. S. (2001). NMDA receptor function in mouse models of Huntington disease. J. Neurosci. Res. 66: 525-539. PubMed citation: 11746372
Chan, H. Y, Warrick, J. M., Gray-Board, G. L., Paulson, H. L. and Bonini, N. M. (2000). Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 9(19): 2811-20. 11092757
Chen-Plotkin, A. S., et al. (2006). Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease. Neurobiol. Dis. 22(2): 233-41. 16442295
Davies, S. W., et al. (1997). Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90(3): 537-48. 9267033
DiFiglia, M., Sapp, E., Chase, K., Schwarz, C., Meloni, A., Young, C., Martin, E., Vonsattel, J. P., Carraway, R. and Reeves, S. A. et al. (1995). Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14: 1075-1081. 7748555
DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P. and Aronin, N. (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277: 1990-1993. 9302293
Dragatsis, I., Levine, M. S. and Zeitlin, S. (2000). Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 26: 300-306. 11062468
Dunah, A. W., et al. (2002). Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease, Science 296: 2238-2243. 11988536
Duyao, M. P., et al. (1995). Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269: 407-410. 7618107
Engelender, S., Sharp, A. H., Colomer, V., Tokito, M. K., Lanahan, A., Worley, P., Holzbaur, E. L. and Ross, C. A. (1997). Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum. Mol. Genet. 6: 2205-2212. 9361024
Fox, J. H., et al. (2004). Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. J Neurochem. 91(2): 413-22. 15447674
Freiman, R.N. and Tjian, R. (2002). Neurodegeneration. A glutamine-rich trail leads to transcription factors. Science 296: 2149-2150. 12077389
Gunawardena, S. and Goldstein, L. S. (2001). Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32, 389-401. 11709151
Gunawardena, S., et al. (2003). Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40: 25-40. 14527431
Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A.S., Hummerich, H. and Nicholson, S. et al. (2003). Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300: 808-812. 12730604
Hockly, E., et al. (2003). Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl. Acad. Sci. 100(4): 2041-6. 12576549
Hodgson, J. G., Agopyan, N., Gutekunst, C .A., Leavitt, B. R., LePiane, F., Singaraja, R., Smith, D. J., Bissada, N., McCutcheon, K. and Nasir, J. et al. (1999). A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23: 181-192. 10402204
Hurd, D. D. and Saxton, W. M. (1996). Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila. Genetics 144: 1075-1085. 8913751
Ishikawa, K., Fujigasaki, H., Saegusa, H., Ohwada, K., Fujita, T., Iwamoto, H., Komatsuzaki, Y., Toru, S., Toriyama, H. and Watanabe, M. et al. (1999). Abundant expression and cytoplasmic aggregations of [alpha]1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum. Mol. Genet. 8: 1185-1193. 10369863
Jackson, G. R., Salecker, I., Dong, X., Yao, X., Arnheim, N., Faber, P. W., MacDonald, M. E. and Zipursky, S. L. (1998). . Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21: 633-642. 9768849
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W. and Glabe, C. G. (2003). Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486-489. 12702875
Kazantsev, A. et al. (2002). A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat. Genet. 30(4): 367-76. 11925563
Kazemi-Esfarjani, P. and Benzer, S. (2000). Genetic suppression of polyglutamine toxicity in Drosophila. Science 287: 1837-1840. 10710314
Kim, Y. J., et al. (2001). Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc. Natl. Acad. Sci. 98(22): 12784-9. 11675509
Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y. and Orr, H. T. (1998). Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95: 41-53. 9778246
Lee, W. C., Yoshihara, M. and Littleton, J. T. (2004). Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc. Natl. Acad. Sci. 101(9): 3224-9. 14978262
Lievens, J. C., Woodman, B., Mahal, A. and Bates, G. P. (2002). Abnormal phosphorylation of synapsin I predicts a neuronal transmission impairment in the R6/2 Huntington's disease transgenic mice. Mol. Cell. Neurosci. 20: 638-648. PubMed citation: 12213445
Li, H., Li, S. H., Johnston, H., Shelbourne, P. F. and Li, X. J. (2000). Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat. Genet. 25: 385-389. 10932179
Li, H., Li, S. H., Yu, Z. X., Shelbourne, P. and Li, X. J. (2001). Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. J. Neurosci. 21: 8473-8481. 11606636
Li, H., Wyman, T., Yu, Z. X., Li, S. H. and Li, X. J. (2004). Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release. Hum. Mol. Genet. 12(16): 2021-30. 12913073
Li, S. H., Gutekunst, C. A., Hersch, S. M. and Li, X. J. (1998). Interaction of huntingtin-associated protein with dynactin p150Glued. J. Neurosci. 18: 1261-1269. 9454836
Li, S. H., et al. (2002). Interaction of Huntington disease protein with transcriptional activator Sp1. Mol. Cell. Biol. 22(5): 1277-87. 11839795
Li, X., Sharp, A. H., Li, S. H., Dawson, T. M., Snyder, S. H. and Ross, C. A. (1996). Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase. Proc. Natl. Acad. Sci. 93: 4839-4844. 8643490
Li, Z., Karlovich, C. A., Fish, M. P., Scott, M. P. and Myers, R. M. (1999). A putative Drosophila homolog of the Huntington's disease gene. Hum. Mol. Genet. 8(9): 1807-1815.
Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H. and Davies, S. W. et al. (1996). Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493-506. 8898202
Marsh, M. and McMahon, H. T. (1999). The structural era of endocytosis. Science 285(5425): 215-20. 10398591
Marsh, J. L., Walker, H., Theisen, H., Zhu, Y. Z., Fielder, T., Purcell, J. and Thompson, L. M. (2000). Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum. Mol. Genet. 9: 13-25. 10587574
Miller, L. C., et al. (2003). Cysteine string protein (CSP) inhibition of N-type calcium channels is blocked by mutant huntingtin. J. Biol. Chem. 278(52): 53072-81. 14570907
Nicniocaill, B., Haraldsson, B., Hansson, O., O'Connor, W.T. and Brundin, P. (2001). Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice. Eur. J. Neurosci. 13: 206-210. PubMed citation: 11135020
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: 811-823. 7774020
Panov, A. V., Lund, S. and Greenamyre, J. T. (2005). Ca2+-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington's disease individuals. Mol. Cell. Biochem. 269: 143-152. PubMed citation: 15786727
Parker, J. A., Connolly, J. B., Wellington, C., Hayden, M., Dausset, J. and Neri, C. (2001). Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc. Natl. Acad. Sci. 98 13318-13323. 11687635
Paulson, H. L., et al. (1997). Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19: 333-344. 9292723
Piccioni, F., Pinton, P., Simeoni, S., Pozzi, P., Fascio, U., Vismara, G., Martini, L., Rizzuto, R. and Poletti, A. (2002). Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J. 16: 1418-1420. 12205033
Puls, I., Jonnakuty, C., LaMonte, B. H., Holzbaur, E. L., Tokito, M., Mann, E., Floeter, M. K., Bidus, K., Drayna, D. and Oh, S. J. et al. (2003). Mutant dynactin in motor neuron disease. Nat. Genet. 33: 455-456. 12627231
Ravikumar, B., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36(6): 585-95. 15146184
Romero, E., et al. (2008). Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length Huntingtin accumulating in the cytoplasm. Neuron 57: 27-40. PubMed citation: 18184562
Sapp, E., Penney, J., Young, A., Aronin, N., Vonsattel, J. P. and DiFiglia, M. (1999). Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J. Neuropathol. Exp. Neurol. 58: 165-173. 10029099
Schaffar, G., et al. (2004). Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol. Cell. 15(1): 95-105. 15225551
Smith, R., Brundin, P. and Li, J. Y. (2005). Synaptic dysfunction in Huntington's disease: a new perspective. Cell. Mol. Life Sci. 62: 1901-1912. PubMed citation: 15968465
Steffan, J. S., et al. (2000). The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. 97(12): 6763-8. 10823891
Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y. Z. and Greenwald, M. et al. (2001). Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739-743. 11607033
Steffan, J. S., et al. (2004). SUMO modification of Huntingtin and Huntington's disease pathology. Science 304(5667): 100-4. 15064418
Stowers, R. S., Megeath, L. J., Gorska-Andrzejak, J., Meinertzhagen, I. A. and Schwarz, T. L. (2002). Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36: 1063-1077. 12495622
Szebenyi, G., Morfini, G. A., Babcock, A., Gould, M., Selkoe, K., Stenoien, D. L., Young, M., Faber, P. W., MacDonald, M. E., McPhaul, M. J. and Brady, S. T. (2003). Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40: 41-52. 14527432
Takano, H. and Gusella, J. F. (2002). The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with Dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci. 3(1): 15. 12379151
Takeyama, K., Ito, S., Yamamoto, A., Tanimoto, H., Furutani, T., Kanuka, H., Miura, M., Tabata, T. and Kato, S. (2002). Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35: 855-864. 12372281
Tanaka, K., Shouguchi-Miyata, J., Miyamoto, N. and Ikeda, J. E. (2004). Novel nuclear shuttle proteins, HDBP1 and HDBP2, bind to neuronal cell-specific cis-regulatory element in the promoter for the human Huntington's disease gene. J. Biol. Chem. 279(8): 7275-86. 14625278
Tang, T. S., et al. (2003). Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39: 227-239. PubMed citation: 12873381
Terry, R. (2000). Cell death or synaptic loss in Alzheimer disease. J. Neuropathol. Exp. Neurol. 59: 1118-1119. 11138931
Turmaine, M., et al. (2000). Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. Proc. Natl. Acad. Sci. 97(14): 8093-7. 10869421
Warrick, J. M., Paulson, H. L., Gray-Board, G. L., Bui, Q. T., Fischbeck, K. H., Pittman, R. N. and Bonini, N. M. (1998). Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93: 939-949. 9635424
Warrick, J. M., Chan, H. Y., Gray-Board, G. L., Chai, Y., Paulson, H. L. and Bonini, N. M. (1999). Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23: 425-428. 10581028
Wellington, C. L., Ellerby, L. M., Gutekunst, C. A., Rogers, D., Warby, S., Graham, R. K., Loubser, O., van Raamsdonk, J., Singaraja, R., Yang, Y. Z., et al. (2002). Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J. Neurosci. 22: 7862-7872. 12223539
Wyss-Coray, T. and Mucke, L. (2002). Inflammation in neurodegenerative disease-a double-edged sword. Neuron 35: 419-432. 12165466
Yoo, S. Y., et al. (2003). SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37: 383-401. 12575948
Yu, Z. X., et al. (2003). Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington's disease. J. Neurosci. 23(6): 2193-202. 12657678
Zeitlin, S., Liu, J. P., Chapman, D. L., Papaioannou, V. E. and Efstratiadis, A. (1995). Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat. Genet. 11: 155-163. 7550343
Zeron, M. M., Hansson, O., Chen, N., Wellington, C. L., Leavitt, B. R., Brundin, P., Hayden, M. R. and Raymond, L. A. (2002). Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33: 849-860. PubMed citation: 11906693
Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V. and Hayden, M. R. et al. (2001). Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293: 493-498. 11408619
date revised: 15 July 2008
Home page: The Interactive Fly © 2003 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
Society for Developmental Biology's Web server.