Astrocytes in neurodegenerative disease

Cold Spring Harbor Perspectives in Biology

Volumn 7, Issue 6, 2015, Pages 1-18

  Phatnani, Hemali ^a   Maniatis, Tom ^a  

^a NewYork Presbyterian Hospital   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL; ASTROCYTE; DEGENERATIVE DISEASE; DEMENTIA; HUMAN; NERVE CELL; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; ASTROCYTES; DEMENTIA; HUMANS; NEURODEGENERATIVE DISEASES; NEURONS;

EID: 84930455971     PISSN: None     EISSN: 19430264     Source Type: Journal    
DOI: 10.1101/cshperspect.a020628     Document Type: Article

References (166)

1. Abramov AY, Canevari L, Duchen MR. 2003. Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23: 5088–5095.
2. Abramov AY, Canevari L, Duchen MR. 2004. b-Amyloid peptides induce mitochondrial dysfunction and oxida-tive stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24: 565–575.
3. Aebischer J, Cassina P, Otsmane B, Moumen A, Seilhean D, Meininger V, Barbeito L, Pettmann B, Raoul C. 2011. IFN-g triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1. Cell Death Differ 18: 754–768.
4. Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ. 2010. Amyloid-b aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal viability. J Neurosci 30: 3326–3338.
5. Allaman I, Belanger M, Magistretti PJ. 2011. Astrocyte-neu-ron metabolic relationships: For better and for worse. Trends Neurosci 34: 76–87.
6. Arregui L, Benitez JA, Razgado LF, Vergara P, Segovia J. 2011. Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington’s disease delays the onset of the motor phenotype. Cell Mol Neurobiol 31: 1229–1243.
7. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. 2011. Alzheimer’s disease. Lancet 377: 1019–1031.
8. Barcia C, Ros CM, Annese V, Gomez A, Ros-Bernal F, Aguado-Yera D, Martinez-Pagan ME, de Pablos V, Fer-nandez-Villalba E, Herrero MT. 2011. IFN-g signaling, with the synergistic contribution of TNF-a, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 2: e142.
9. Barres BA. 2008. The mystery and magic of glia: A perspective on their roles in health and disease. Neuron 60: 430–440.
10. Battaglia G, Cannella M, Riozzi B, Orobello S, Maat-Schie-man ML, Aronica E, Busceti CL, Ciarmiello A, Alberti S, Amico Eb, et al. 2011. Early defect of transforming growth factor b1 formation in Huntington’s disease. J Cell Mol Med 15: 555–571.
11. Belanger M, Magistretti PJ. 2009. The role of astroglia in neuroprotection. Dialogues Clin Neurosci 11: 281–295.
12. Boillee S, Vande Velde C, Cleveland DW. 2006. ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron 52: 39–59.
13. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, et al. 2003. Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science 299: 256–259.
14. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. 2003. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24: 197– 211.
15. Braak H, Sastre M, Del Tredici K. 2007. Development of a-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 114: 231–241.
16. Bradford J, Shin JY, Roberts M, Wang CE, Li XJ, Li S. 2009. Expression of mutant huntingtin in mouse brain astro-cytes causes age-dependent neurological symptoms. Proc Natl Acad Sci 106: 22480–22485.
17. Bradford J, Shin JY, Roberts M, Wang CE, Sheng G, Li S, Li XJ. 2010. Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem 285: 10653–10661.
18. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR. 2005. Inhibition of astroglial nuclear factor kB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202: 145–156.
19. Brambilla R, Hurtado A, Persaud T, Esham K, Pearse DD, Oudega M, Bethea JR. 2009a. Transgenic inhibition of astroglial NF-kB leads to increased axonal sparing and sprouting following spinal cord injury. J Neurochem 110: 765–778.
20. Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, Ivanov D, Nathanson L, Barnum SR, Bethea JR. 2009b. Transgenic inhibition of astroglial NF-kB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol 182: 2628–2640.
21. Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A. 2001. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27: 117–120.
22. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, et al. 1997. ALS-linked SOD1 mutant G85R mediates damage toastrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18: 327–338.
23. Butterworth RF. 2010. Altered glial-neuronal crosstalk: Cornerstone in the pathogenesis of hepatic encephalopathy. Neurochem Int 57: 383–388.
24. Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP, Beckman JS, Barbeito L, et al. 2008. Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: Prevention by mitochondrial-targeted an-tioxidants. J Neurosci 28: 4115–4122.
25. Chou SY, Weng JY, Lai HL, Liao F, Sun SH, Tu PH, Dickson DW, Chern Y. 2008. Expanded-polyglutamine huntingtin protein suppresses the secretion and production of a che-mokine (CCL5/RANTES) by astrocytes. J Neurosci 28: 3277–3290.
26. Chung WS, Barres BA. 2012. The role of glial cells in synapse elimination. Curr Opin Neurobiol 22: 438–445.
27. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, et al. 2003. Wild-type nonneuronal cells extend sur-vival of SOD1 mutant motor neurons in ALS mice. Science 302: 113–117.
28. Crosio C, Valle C, Casciati A, Iaccarino C, Carri MT. 2011. Astroglial inhibition of NF-kB does not ameliorate disease onset and progression in a mouse model for amyo-trophic lateral sclerosis (ALS). PLoS ONE 6: e17187.
29. Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F. 1993. Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52: 1–6.
30. Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. 2007. Non-cell-autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10: 608–614.
31. Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC. 2008. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3: 637–648.
32. Dvoriantchikova G, Barakat D, Brambilla R, Agudelo C, Hernandez E, Bethea JR, Shestopalov VI, Ivanov D. 2009. Inactivation of astroglial NF-kB promotes survival of retinal neurons following ischemic injury. Eur J Neuro-sci 30: 175–185.
33. Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, Dufour N, Guillermier M, Brouillet E, Hantraye P, et al. 2010. In vivo expression of polyglutamine-expand-ed huntingtin by mouse striatal astrocytes impairs gluta-mate transport: A correlation with Huntington’s disease subjects. Hum Mol Genet 19: 3053–3067.
34. Felipo V, Butterworth RF. 2002. Neurobiology of ammonia. Prog Neurobiol 67: 259–279.
35. Ferraiuolo L, Higginbottom A, Heath PR, Barber S, Green-ald D, Kirby J, Shaw PJ. 2011. Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 134: 2627–2641.
36. Forsberg K, Andersen PM, Marklund SL, Brannstrom T. 2011. Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis. Acta Neuropathol 121: 623–634.
37. Gan L, Johnson DA, Johnson JA. 2010. Keap1-Nrf2 activation in the presence and absence of DJ-1. Eur J Neurosci 31: 967–977.
38. Gan L, Vargas MR, Johnson DA, Johnson JA. 2012. Astro-cyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS inthe a-synuclein mutant (A53T) mouse model. J Neurosci 32: 17775–17787.
39. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. 2011. Astrocytes are important mediators of Ab-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2: e167.
40. Gu XL, Long CX, Sun L, Xie C, Lin X, Cai H. 2010. Astro-cytic expression of Parkinson’s disease-related A53T a-synuclein causes neurodegeneration in mice. Mol Brain 3: 12.
41. Guo H, Lai L, Butchbach ME, Stockinger MP, Shan X, Bishop GA, Lin CL. 2003. Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 12: 2519–2532.
42. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. 1994. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264: 1772–1775.
43. Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, et al. 2011. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29: 824–828.
44. Haidet-Phillips AM, Gross SK, Williams T, Tuteja A, Sherman A, Ko M, Jeong YH, Wong PC, Maragakis NJ. 2013. Altered astrocytic expression of TDP-43 does not influence motor neuron survival. Exp Neurol 250: 250–259.
45. Halliday GM, Stevens CH. 2011. Glia: Initiators and pro-gressors of pathology in Parkinson’s disease. Mov Disord 26: 6–17.
46. Hardy J, Selkoe DJ. 2002. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 297: 353–356.
47. Hashida K, Kitao Y, Sudo H, Awa Y, Maeda S, Mori K, Takahashi R, Iinuma M, Hori O. 2012. ATF6a promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson’s disease. PLoS ONE 7: e47950.
48. Hashioka S, Klegeris A, Schwab C, McGeer PL. 2009. Inter-feron-g-dependent cytotoxic activation of human astro-cytes and astrocytoma cells. Neurobiol Aging 30: 1924–1935.
49. Hashioka S, Klegeris A, Schwab C, Yu S, McGeer PL. 2010. Differential expression of interferon-g receptor on human glial cells in vivo and in vitro. J Neuroimmunol 225: 91–99.
50. Hashioka S, Klegeris A, Qing H, McGeer PL. 2011. STAT3 inhibitors attenuate interferon-g-induced neurotoxicity and inflammatory molecule production byhuman astro-cytes. Neurobiol Dis 41: 299–307.
51. Haussinger D, Schliess F. 2008. Pathogenetic mechanisms of hepatic encephalopathy. Gut 57: 1156–1165.
52. Hawkes CH, Del Tredici K, Braak H. 2007. Parkinson’s disease: A dual-hit hypothesis. Neuropathol Appl Neurobiol 33: 599–614.
53. Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV. 2008. S TAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28: 7231–7243.
54. Hewitt C, Kirby J, Highley JR, Hartley JA, Hibberd R, Hol-linger HC, Williams TL, Ince PG, McDermott CJ, Shaw PJ. 2010. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 67: 455–461.
55. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, et al. 2002. Focal loss of the glutamate transporter EAAT2 in a transgenic rat modelof SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci 99: 1604–1609.
56. Hsiao HY, Chen YC, Chen HM, Tu PH, Chern Y. 2013. A critical role of astrocyte-mediated nuclear factor-kB-de-pendent inflammation in Huntington’s disease. Hum Mol Genet 22: 1826–1842.
57. Ilieva H, Polymenidou M, Cleveland DW. 2009. Non-cell-autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187: 761–772.
58. Imai Y, Soda M, Takahashi R. 2000. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275: 35661–35664.
59. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. 2001. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105: 891–902.
60. Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogen-raad CC. 2008. Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci 28: 2075–2088.
61. Jana A, Pahan K. 2010. Fibrillaramyloid-b-activated human astroglia kill primary human neurons via neutral sphin-gomyelinase: Implications for Alzheimer’s disease. J Neu-rosci 30: 12676–12689.
62. Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR, Chen PC. 2008. The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurode-generation. Ann NY Acad Sci 1147: 61–69.
63. Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA, Ming GL, Song H. 2012. Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington’s disease patient cells. Mol Brain 5: 17.
64. Kang SH, Li Y, F ukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE. 2013. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16: 571–579.
65. Khakh BS, Sofroniew MV. 2014. Astrocytes and Hunting-ton’s Disease. ACS Chem Neurosci 5: 494–496.
66. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Har-diman O, Burrell JR, Zoing MC. 2011. Amyotrophic lateral sclerosis. Lancet 377: 942–955.
67. Kimelberg HK. 2004. The problem of astrocyte identity. Neurochem Int 45: 191–202.
68. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. 1998. Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature 392: 605–608.
69. Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, et al. 2004. Apoli-poprotein E promotes astrocyte colocalization and degradation of deposited amyloid-b peptides. Nat Med 10: 719–726.
70. Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ. 2009. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323: 1211–1215.
71. Ledesma MD, Galvan C,HelliasB, DottiC,Jensen PH. 2002. Astrocytic but not neuronal increased expression and redistribution of parkin during unfolded protein stress. J Neurochem 83: 1431–1440.
72. Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ. 2010. Direct transfer of a-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285: 9262–9272.
73. Lee M, McGeer E, McGeer PL. 2013a. Neurotoxins released from interferon-g-stimulated human astrocytes. Neuro-science 229: 164–175.
74. Lee W, Reyes RC, Gottipati MK, Lewis K, Lesort M, Parpura V, Gray M. 2013b. Enhanced Ca2þ-dependent glutamate release from astrocytes of the BACHD Huntington’s disease mouse model. Neurobiol Dis 58: 192–199.
75. Lees AJ, Hardy J, Revesz T. 2009. Parkinson’s disease. Lancet 373: 2055–2066.
76. L’Episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B. 2011. A Wnt1 regulated Frizzled-1/b-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron–astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6: 49.
77. Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ. 2008. Focal transplantation-based as-trocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 11: 1294–1301.
78. Li R, Johnson AB, Salomons G, Goldman JE, Naidu S, Quin-lan R, Cree B, Ruyle SZ, Banwell B, D’Hooghe M, et al. 2005. Glialfibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57: 310–326.
79. Lino MM, Schneider C, Caroni P. 2002. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J Neuro-sci 22: 4825–4832.
80. MacCormac LP, Muqit MM, Faulkes DJ, Wood NW, Latch-man DS. 2004. Reduction in endogenous parkin levels renders glial cells sensitive to both caspase-dependent and caspase-independent cell death. Eur J Neurosci 20: 2038–2048.
81. Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K, Roeber S, Kretzschmar HA, Cairns NJ, Neumann M. 2011. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 121: 207–218.
82. Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH. 2008. Non-cell-autonomous effect of human SOD1G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3: 649–657.
83. Martorana F, Brambilla L, Valori CF, Bergamaschi C, Ron-coroni C, Aronica E, Volterra A, Bezzi P, Rossi D. 2012. The BH4 domain of Bcl-XL rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating in-tracellular calcium signals. Hum Mol Genet 21: 826–840.
84. Mei X, Ezan P, Giaume C, Koulakoff A. 2010. Astroglial connexin immunoreactivity is specifically altered at b-amyloid plaques in b-amyloid precursor protein/prese-nilin1 mice. Neuroscience 171: 92–105.
85. Mena MA, Garcia de Yebenes J. 2008. Glial cells as players in parkinsonism: The “good,” the “bad,” and the “mysterious” glia. Neuroscientist 14: 544–560.
86. Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, Ditsworth D, Lagier-Tourenne C, Smith RA, Ravits J, et al. 2014. Direct conversion of patient fibro-blasts demonstrates non-cell-autonomous toxicity of as-trocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci 111: 829–832.
87. Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, Barres BA, Rowitch DH. 2012. Astro-cytes and disease: A neurodevelopmental perspective. Genes Dev 26: 891–907.
88. Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T. 2010. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia 58: 300–314.
89. Mullett SJ, Hinkle DA. 2009. DJ-1 knock-down in astrocytes impairs astrocyte-mediated neuroprotection against ro-tenone. Neurobiol Dis 33: 28–36.
90. Nagai M, Aoki M, Miyoshi I, Kato M, Pasinelli P, Kasai N, Brown RH Jr, Itoyama Y. 2001. Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: Associated mutations develop motor neuron disease. J Neurosci 21: 9246–9254.
91. Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wich-terle H, Przedborski S. 2007. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10: 615–622.
92. Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY. 2003. Astrocytes accumulate Ab42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971: 197–209.
93. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J. 2004. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neuro-biol Aging 25: 663–674.
94. Nagy JI, Li W, Hertzberg EL, Marotta CA. 1996. Elevated connexin43 immunoreactivity at sites ofamyloid plaques in Alzheimer’s disease. Brain Res 717: 173–178.
95. Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, Lee CS, McKenzie J, McCormick S, Samii A, Troiano A, et al. 2009. Longitudinal progression of sporadic Parkinson’s disease: A multi-tracer positron emission tomography study. Brain 132: 2970–2979.
96. Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM, Clark CM, Grossman M, Miller BL, Trojanowski JQ, et al. 2007. TDP-43-pos-itive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuro-pathol Exp Neurol 66: 177–183.
97. Nishihira Y, Tan CF, Onodera O, Toyoshima Y, Yamada M, Morita T, Nishizawa M, Kakita A, Takahashi H. 2008. Sporadic amyotrophic lateral sclerosis: Two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116: 169–182.
98. Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, et al. 2006. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12: 829–834.
99. Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. 2010. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58: 831–838.
100. Oliveira JM. 2010. Mitochondrial bioenergetics and dynamics in Huntington’s disease: Tripartite synapses and selective striatal degeneration. J Bioenerg Biomembr 42: 227–234.
101. Orellana JA, Froger N, Ezan P, Jiang JX, Bennett MV, Naus CC, Giaume C, Saez JC. 2011a. ATP and glutamate re-leased via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemi-channels. J Neurochem 118: 826–840.
102. Orellana JA, Shoji KF, Abudara V, Ezan P, Amigou E, Saez PJ, Jiang JX, Naus CC, Saez JC, Giaume C. 2011b. Amyloid b-induced death in neurons involves glial and neuronal hemichannels. J Neurosci 31: 4962–4977.
103. Papadeas ST, Kraig SE, O’Banion C, Lepore AC, Maragakis NJ. 2011. Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc Natl Acad Sci 108: 17803–17808.
104. Paradisi S, Sacchetti B, Balduzzi M, Gaudi S, Malchiodi-Albedi F. 2004. Astrocyte modulation of in vitro b-amy-loid neurotoxicity. Glia 46: 252–260.
105. Pardo AC, Wong V, Benson LM, Dykes M, Tanaka K, Roth-stein JD, Maragakis NJ. 2006. Loss of the astrocyte gluta-mate transporter GLT1 modifies disease in SOD1G93A mice. Exp Neurol 201: 120–130.
106. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG. 2005. Astrocytic purinergic signaling coordinates synap-tic networks. Science 310: 113–116.
107. Pasinelli P, Houseweart MK, Brown RH Jr, Cleveland DW. 2000. Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-medi-ated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci 97: 13901–13906.
108. Perea G, Navarrete M, Araque A. 2009. Tripartite synapses: Astrocytes process and control synaptic information. Trends Neurosci 32: 421–431.
109. Phatnani HP, Guarnieri P, Friedman BA, Carrasco MA, Muratet M, O’Keeffe S, Nwakeze C, Pauli-Behn F, New-berry KM, Meadows SK, et al. 2013. Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci 110: E756–E765.
110. Pihlaja R, Koistinaho J, Malm T, Sikkila H, Vainio S, Kois-tinaho M. 2008. Transplanted astrocytes internalize deposited b-amyloid peptides in a transgenic mouse model of Alzheimer’s disease. Glia 56: 154–163.
111. Pihlaja R, Koistinaho J, Kauppinen R, Sandholm J, Tanila H, Koistinaho M. 2011. Multiple cellular and molecular mechanisms are involved in human Ab clearance by transplanted adult astrocytes. Glia 59: 1643–1657.
112. Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA. 2001. Neuron-specific expression of mutant super-oxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21: 3369–3374.
113. Pun S, Santos AF, Saxena S, Xu L, Caroni P. 2006. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9: 408–419.
114. Quinlan RA, Brenner M, Goldman JE, Messing A. 2007. GFAP and its role in Alexander disease. Exp Cell Res 313: 2077–2087.
115. Robertson J, Bilbao J, Zinman L, Hazrati LN, Tokuhiro S, Sato C, Moreno D, Strome R, Mackenzie IR, Rogaeva E. 2011. A novel double mutation in FUS gene causing sporadic ALS. Neurobiol Aging 32: 553 e527–530.
116. Ross CA, Tabrizi SJ. 2011. Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet Neurol 10: 83–98.
117. Rossi D, Brambilla L, Valori CF, Roncoroni C, Crugnola A, Yokota T, Bredesen DE, Volterra A. 2008. Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ 15: 1691–1700.
118. Rothstein JD, Martin LJ, Kuncl RW. 1992. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326: 1464–1468.
119. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. 1995. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38: 73–84.
120. Sagredo O, Gonzalez S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I, Romero JP, Tolon RM, Mechoulam R, Brouillet E, et al. 2009. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxic-ity: Relevance for Huntington’s disease. Glia 57: 1154–1167.
121. Saito VM, Rezende RM, Teixeira AL. 2012. Cannabinoid modulation of neuroinflammatory disorders. Curr Neu-ropharmacol 10: 159–166.
122. Sasabe J, Chiba T, Yamada M, Okamoto K, Nishimoto I, Matsuoka M, Aiso S. 2007. D-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26: 4149–4159.
123. Sasabe J, Miyoshi Y, Suzuki M, Mita M, Konno R, Matsuoka M, Hamase K, Aiso S. 2012. D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc Natl Acad Sci 109: 627–632.
124. Schon EA, Przedborski S. 2011. Mitochondria: The next (neurode)generation. Neuron 70: 1033–1053.
125. Seilhean D, Cazeneuve C, Thuries V, Russaouen O, Millecamps S, Salachas F, Meininger V, Leguern E, Duyckaerts C. 2009. Accumulation of TDP-43 and a-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol 118: 561–573.
126. Selkoe DJ, American College of Physicians, American Physiological Society. 2004. Alzheimer disease: Mechanistic understanding predicts novel therapies. Ann Intern Med 140: 627–638.
127. Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, Burr K, Haghi G, Story D, Nishimura AL, et al. 2013. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci 110: 4697–4702.
128. Shibata N, Kakita A, Takahashi H, Ihara Y, Nobukuni K, Fujimura H, Sakoda S, Sasaki S, Iwata M, Morikawa S, et al. 2009. Activation of signal transducer and activator of transcription-3 in the spinal cord of sporadic amyo-trophic lateral sclerosis patients. Neurodegener Dis 6: 118–126.
129. Shibata N, Yamamoto T, Hiroi A, Omi Y, Kato Y, Kobayashi M. 2010. Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosis. Neuropa-thology 30: 353–360.
130. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, et al. 2000. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25: 302–305.
131. Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ. 2005. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 171: 1001–1012.
132. Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman AB, Aschner M. 2011. Role of astrocytes in brain function and disease. Toxicol Pathol 39: 115–123.
133. Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Savva G, Brayne C, Wharton SB, Function MRCC, et al. 2010. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31: 578–590.
134. Skorupa A, King MA, Aparicio IM, Dussmann H, Cough-lan K, Breen B, Kieran D, Concannon CG, Marin P, Prehn JH. 2012. Motoneurons secrete angiogenin to induce RNA cleavage in astroglia. J Neurosci 32: 5024–5038.
135. Skorupa A, Urbach S, Vigy O, King MA, Chaumont-Dubel S, Prehn JH, Marin P. 2013. Angiogenin induces modifications in the astrocyte secretome: Relevance to amyotro-phic lateral sclerosis. J Proteomics 91: 274–285.
136. Small SA, Duff K. 2008. Linking Ab and tau in late-onset Alzheimer’s disease: A dual pathway hypothesis. Neuron 60: 534–542.
137. Sofroniew MV. 2009. Molecular dissection of reactive astro-gliosis and glial scar formation. Trends Neurosci 32: 638– 647.
138. Sofroniew MV, Vinters HV. 2010. Astrocytes: Biology and pathology. Acta Neuropathol 119: 7–35.
139. Song YJ, Halliday GM, Holton JL, Lashley T, O’Sullivan SS, McCann H, Lees AJ, Ozawa T, Williams DR, Lockhart PJ, et al. 2009. Degeneration in different parkinso-nian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 68: 1073–1083.
140. Stevens B. 2008. Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neuro-Signals 16: 278–288.
141. Stieber A, Gonatas JO, Gonatas NK. 2000. Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuro-nal and astrocytic perikarya of mice expressing the SOD1G93A mutation of familial amyotrophic lateral sclerosis. J Neurol Sci 177: 114–123.
142. Takeuchi H, Mizoguchi H, Doi Y, Jin S, Noda M, Liang J, Li H, Zhou Y, Mori R, Yasuoka S, et al. 2011. Blockadeof gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer’s disease. PLoS ONE 6: e21108.
143. Tong J, Huang C, Bi F, Wu Q, Huang B, Liu X, Li F, Zhou H, Xia XG. 2013. Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J 32: 1917–1926.
144. Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, Anderson MA, Mody I, Olsen ML, Sofroniew MV, et al. 2014. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci 17: 694–703.
145. Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Mar-ques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, et al. 2012. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337: 358–362.
146. Tzeng SF, Hsiao HY, Mak OT. 2005. Prostaglandins and cyclooxygenases in glial cells during brain inflammation. Curr Drug Targets Inflamm Allergy 4: 335–340.
147. Valenza M, Cattaneo E. 2011. Emerging roles for cholesterol in Huntington’s disease. Trends Neurosci 34: 474–486.
148. Valenza M, Leoni V, Karasinska JM, Petricca L, Fan J, Carroll J, Pouladi MA, Fossale E, Nguyen HP, Riess O, et al. 2010. Cholesterol defectis marked across multiple rodent models of Huntington’s disease and is manifest in astrocytes. J Neurosci 30: 10844–10850.
149. Van Damme P, Bogaert E, Dewil M, Hersmus N, Kiraly D, Scheveneels W, Bockx I, Braeken D, Verpoorten N, Verho-even K, et al. 2007. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxic-ity. Proc Natl Acad Sci 104: 14825–14830.
150. Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA. 2008. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyo-trophic lateral sclerosis. J Neurosci 28: 13574–13581.
151. Vis JC, Nicholson LF, Faull RL, Evans WH, Severs NJ, Green CR. 1998. Connexin expression in Huntington’s diseased human brain. Cell Biol Int 22: 837–847.
152. Wagner B, Natarajan A, Grunaug S, Kroismayr R, Wagner EF, Sibilia M. 2006. Neuronal survival depends on EGFR signaling in cortical but not midbrain astrocytes. EMBO J 25: 752–762.
153. Walker FO. 2007. Huntington’s disease. Lancet 369: 218–228.
154. Walsh DM, Selkoe DJ. 2004. Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44: 181–193.
155. Wang L, Gutmann DH, Roos RP. 2011. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum Mol Genet 20: 286–293.
156. Wang L, Lin F, Wang J, Wu J, Han R, Zhu L, Zhang G, DiFiglia M, Qin Z. 2012. Truncated N-terminal hunting-tin fragment with expanded-polyglutamine (htt552– 100Q) suppresses brain-derived neurotrophic factor transcription in astrocytes. Acta Biochim Biophys Sinica 44: 249–258.
157. Williamson TP, Johnson DA, Johnson JA. 2012. Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology 33: 272–279.
158. Wojtowicz AM, Dvorzhak A, Semtner M, Grantyn R. 2013. Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3. Front Neural Circuits 7: 188.
159. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL. 1995. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14: 1105–1116.
160. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J. 2003. Adult mouse astro-cytes degrade amyloid-b in vitro and in situ. Nat Med 9: 453–457.
161. Yamamoto-Watanabe Y, Watanabe M, Okamoto K, Fujita Y, Jackson M, Ikeda M, Nakazato Y, Ikeda Y, Matsubara E, Kawarabayashi T, et al. 2010. A Japanese ALS6 family with mutation R521C in the FUS/TLS gene: A clinical, pathological and genetic report. J Neurol Sci 296: 59–63.
162. Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yama-shita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. 2008. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11: 251–253.
163. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA. 2012. Genomic analysis of reactive astroglio-sis. J Neurosci 32: 6391–6410.
164. Zhang Y, Barres BA. 2010. Astrocyte heterogeneity: An underappreciated topic in neurobiology. Curr Opin Neuro-biol 20: 588–594.
165. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. 2000. Parkin functions as an E2-dependent ubiqui-tin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci 97: 13354–13359.
166. Zhang H, Tan CF, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K. 2008. TDP-43-immunoreactive neuro-nal and glial inclusions in the neostriatum in amyotro-phic lateral sclerosis with and without dementia. Acta Neuropathol 115: 115–122.