14. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, et al. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277: 1990–1993. 15. Trushina E, Heldebrant MP, Perez-Terzic CM, Bortolon R, Kovtun IV, et al. (2003) Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington’s disease. Proc Natl Acad Sci U S A 100: 12171–12176. 16. Li H, Li SH, Yu ZX, Shelbourne P, Li XJ (2001) Huntingtin aggregate- associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci 21: 8473–8481. 17. Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4: 446–456. 18. Nakayama AY, Luo L (2000) Intracellular signaling pathways that regulate dendritic spine morphogenesis. Hippocampus 10: 582–586. 19. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, et al. (1996) Phosphorylation and activation of myosin by Rho-associated kinase (Rho- kinase). J Biol Chem 271: 20246–20249. 20. Shao J, Welch WJ, Diprospero NA, Diamond MI (2008) Phosphorylation of Profilin by ROCK1 Regulates Polyglutamine Aggregation. Mol Cell Biol. 21. Shao J, Welch WJ, Diamond MI (2008) ROCK and PRK-2 mediate the inhibitory effect of Y-27632 on polyglutamine aggregation. FEBS Lett 582: 1637–1642. 22. Pollitt SK, Pallos J, Shao J, Desai UA, Ma AA, et al. (2003) A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron 40: 685–694. 23. Paoletti P, Vila I, Rife M, Lizcano JM, Alberch J, et al. (2008) Dopaminergic and glutamatergic signaling crosstalk in Huntington’s disease neurodegenera- tion: the role of p25/cyclin-dependent kinase 5. J Neurosci 28: 10090–10101. 24. Robinson P, Lebel M, Cyr M (2008) Dopamine D1 receptor-mediated aggregation of N-terminal fragments of mutant huntingtin and cell death in a neuroblastoma cell line. Neuroscience 153: 762–772. 25. Tang TS, Chen X, Liu J, Bezprozvanny I (2007) Dopaminergic signaling and striatal neurodegeneration in Huntington’s disease. J Neurosci 27: 7899–7910. 26. Stoof JC, Kebabian JW (1981) Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature 294: 366–368. 27. Senogles SE (2000) The D2s dopamine receptor stimulates phospholipase D activity: a novel signaling pathway for dopamine. Mol Pharmacol 58: 455–462. 28. Heredia L, Helguera P, de Olmos S, Kedikian G, Sola Vigo F, et al. (2006) Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer’s disease. J Neurosci 26: 6533–6542. 29. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, et al. (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A 85: 5733–5737. 30. Yohrling GJt, Jiang GC, DeJohn MM, Miller DW, Young AB, et al. (2003) Analysis of cellular, transgenic and human models of Huntington’s disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology. Brain Res Mol Brain Res 119: 28–36. 31. Sapp E, Ge P, Aizawa H, Bird E, Penney J, et al. (1995) Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington’s disease using high resolution image analysis. Neuroscience 64: 397–404. 32. Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, et al. (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19: 2522–2534. 33. Yang SH, Cheng PH, Banta H, Piotrowska-Nitsche K, Yang JJ, et al. (2008) Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453: 921–924. 34. Tallaksen-Greene SJ, Crouse AB, Hunter JM, Detloff PJ, Albin RL (2005) Neuronal intranuclear inclusions and neuropil aggregates in HdhCAG(150) knockin mice. Neuroscience 131: 843–852. 35. Lee WC, Yoshihara M, Littleton JT (2004) Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc Natl Acad Sci U S A 101: 3224–3229. Dopamine/D2 Receptor and HD 36. Wang CE, Zhou H, McGuire JR, Cerullo V, Lee B, et al. (2008) Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 181: 803–816. 37. Albin RL, Reiner A, Anderson KD, Dure LSt, Handelin B, et al. (1992) Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol 31: 425–430. 38. Albin RL, Young AB, Penney JB, Handelin B, Balfour R, et al. (1990) Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington’s disease. N Engl J Med 322: 1293–1298. 39. Parish CL, Finkelstein DI, Drago J, Borrelli E, Horne MK (2001) The role of dopamine receptors in regulating the size of axonal arbors. J Neurosci 21: 5147–5157. 40. Parish CL, Stanic D, Drago J, Borrelli E, Finkelstein DI, et al. (2002) Effects of long-term treatment with dopamine receptor agonists and antagonists on terminal arbor size. Eur J Neurosci 16: 787–794. 41. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78: 189–225. 42. Yan Z, Feng J, Fienberg AA, Greengard P (1999) D(2) dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons. Proc Natl Acad Sci U S A 96: 11607–11612. 43. Brami-Cherrier K, Valjent E, Garcia M, Pages C, Hipskind RA, et al. (2002) Dopamine induces a PI3-kinase-independent activation of Akt in striatal neurons: a new route to cAMP response element-binding protein phosphory- lation. J Neurosci 22: 8911–8921. 44. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, et al. (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122: 261–273. 45. Jalink K, Eichholtz T, Postma FR, van Corven EJ, Moolenaar WH (1993) Lysophosphatidic acid induces neuronal shape changes via a novel, receptor- mediated signaling pathway: similarity to thrombin action. Cell Growth Differ 4: 247–255. 46. Jalink K, van Corven EJ, Hengeveld T, Morii N, Narumiya S, et al. (1994) Inhibition of lysophosphatidate- and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J Cell Biol 126: 801–810. 47. Kranenburg O, Poland M, van Horck FP, Drechsel D, Hall A, et al. (1999) Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction. Mol Biol Cell 10: 1851–1857. 48. Barnes WG, Reiter E, Violin JD, Ren XR, Milligan G, et al. (2005) beta- Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem 280: 8041–8050. 49. Macey TA, Gurevich VV, Neve KA (2004) Preferential Interaction between the dopamine D2 receptor and Arrestin2 in neostriatal neurons. Mol Pharmacol 66: 1635–1642. 50. Hirose M, Ishizaki T, Watanabe N, Uehata M, Kranenburg O, et al. (1998) Molecular dissection of the Rho-associated protein kinase (p160ROCK)- regulated neurite remodeling in neuroblastoma N1E-115 cells. J Cell Biol 141: 1625–1636. 51. Bauer PO, Wong HK, Oyama F, Goswami A, Okuno M, et al. (2009) Inhibition of rho-kinases enhances the degradation of mutant huntingtin. J Biol Chem. 52. Wettschureck N, Offermanns S (2002) Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J Mol Med 80: 629–638. 53. Bito H, Furuyashiki T, Ishihara H, Shibasaki Y, Ohashi K, et al. (2000) A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron 26: 431–441. 54. Zhou Y, Su Y, Li B, Liu F, Ryder JW, et al. (2003) Nonsteroidal anti- inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 302: 1215–1217. 55. Adam OR, Jankovic J (2008) Symptomatic treatment of Huntington disease. Neurotherapeutics 5: 181–197. 56. Correll CU (2007) Acute and long-term adverse effects of antipsychotics. CNS Spectr 12: 10–14. PLoS ONE | www.plosone.org 11 December 2009 | Volume 4 | Issue 12 | e8287