Absence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia Article Received: 19 April 2005 Accepted: 13 September 2005 Summary.
α-Synuclein is a major constituent of glial cytoplasmic inclusions (GCIs), which are pathognomic for multiple system atrophy (MSA). We have previously demonstrated that in normal human brain, α-synuclein mRNA has a restricted pattern of neuronal expression and no apparent glial expression. The current study used double-label
in situ hybridization to determine if α-synuclein mRNA is expressed by oligodendroglia of MSA cases. Analysis of MSA brain tissue revealed depletion of regional signal for this transcript in many brain areas due to extensive neurodegeneration. Cellular analysis of oligodendroglia in crus cerebri, a GCI-rich region ventral to substantia nigra, revealed an absence of α-synuclein mRNA signal in control and MSA cases. However, an abundance of this transcript was detected in melanin-containing neurons of substantia nigra. Therefore, oligodendroglia do not express α-synuclein mRNA in control and MSA cases suggesting that involvement of α-synuclein in GCI pathology of MSA is due to its ectopic presence in oligodendroglia. Keywords: Glial cytoplasmic inclusion, in situ hybridization, synucleinopathy. References Arima, K, Ueda, K, Sunohara, N, Arakawa, K, Hirai, S, Nakamura, M, Tonozuka-Uehara, H, Kawai, M 1998 NACP/alpha-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol (Berl) 96 439 444 Google Scholar Borghi, R, Marchese, R, Negro, A, Marinelli, L, Forloni, G, Zaccheo, D, Abbruzzese, G, Tabaton, M 2000 Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett 287 65 67 CrossRef PubMed Google Scholar Counihan, TJ, Landwehrmeyer, B, Standaert, DG, Kosinski, CM, Scherzer, CR, Daggett, LP, Velicelebi, G, Young, AB, Penney, JB 1998 Expression of N-methyl-D-aspartate receptor subunit mRNA in the human brain: mesencephalic dopaminergic neurons. J Comp Neurol 390 91 101 CrossRef PubMed Google Scholar El-Agnaf, OM, Salem, SA, Paleologou, KE, Cooper, LJ, Fullwood, NJ, Gibson, MJ, Curran, MD, Court, JA, Mann, DM, Ikeda, S, Cookson, MR, Hardy, J, Allsop, D 2003 Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. Faseb J 17 1945 1947 PubMed Google Scholar Farrer, M, Kachergus, J, Forno, L, Lincoln, S, Wang, DS, Hulihan, M, Maraganore, D, Gwinn-Hardy, K, Wszolek, Z, Dickson, D, Langston, JW 2004 Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55 174 179 CrossRef PubMed Google Scholar Fujiwara, H, Hasegawa, M, Dohmae, N, Kawashima, A, Masliah, E, Goldberg, MS, Shen, J, Takio, K, Iwatsubo, T 2002 alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4 160 164 CrossRef PubMed Google Scholar Gilman, S, Low, PA, Quinn, N, Albanese, A, Ben-Shlomo, Y, Fowler, CJ, Kaufmann, H, Klockgether, T, Lang, AE, Lantos, PL, Litvan, I, Mathias, CJ, Oliver, E, Robertson, D, Schatz, I, Wenning, GK 1999 Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 163 94 98 CrossRef PubMed Google Scholar Gwinn-Hardy, K, Mehta, ND, Farrer, M, Maraganore, D, Muenter, M, Yen, SH, Hardy, J, Dickson, DW 2000 Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol (Berl) 99 663 672 Google Scholar Honjyo, Y, Kawamoto, Y, Nakamura, S, Nakano, S, Akiguchi, I 2001 P39 immunoreactivity in glial cytoplasmic inclusions in brains with multiple system atrophy. Acta Neuropathol (Berl) 101 190 194 Google Scholar Irizarry, MC, Kim, TW, McNamara, M, Tanzi, RE, George, JM, Clayton, DF, Hyman, BT 1996 Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system. J Neuropathol Exp Neurol 55 889 895 PubMed Google Scholar Iwai, A, Masliah, E, Yoshimoto, M, Ge, N, Flanagan, L, de Silva, HA, Kittel, A, Saitoh, T 1995 The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14 467 475 CrossRef PubMed Google Scholar Jellinger, KA, Seppi, K, Wenning, GK 2005 Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 20 S29 S36 PubMed Google Scholar Kahle, PJ, Neumann, M, Ozmen, L, Muller, V, Jacobsen, H, Spooren, W, Fuss, B, Mallon, B, Macklin, WB, Fujiwara, H, Hasegawa, M, Iwatsubo, T, Kretzschmar, HA, Haass, C 2002 Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3 583 588 CrossRef PubMed Google Scholar Kerner, JA, Standaert, DG, Penney, JB, Young, AB, Landwehrmeyer, GB 1998 Simultaneous isotopic and nonisotopic in situ hybridization histochemistry with cRNA probes. Brain Res Protocols 3 22 32 CrossRef Google Scholar Lantos, PL 1998 The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 57 1099 1111 PubMed Google Scholar Maroteaux, L, Campanelli, JT, Scheller, RH 1988 Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8 2804 2815 PubMed Google Scholar Miller, DW, Cookson, MR, Dickson, DW 2004a Glial cell inclusions and the pathogenesis of neurodegenerative diseases. Neuron Glia Biol 1 13 21 CrossRef Google Scholar Miller, DW, Hague, SM, Clarimon, J, Baptista, M, Gwinn-Hardy, K, Cookson, MR, Singleton, AB 2004b Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62 1835 1838 Google Scholar Mori, F, Tanji, K, Yoshimoto, M, Takahashi, H, Wakabayashi, K 2002 Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol 176 98 104 CrossRef PubMed Google Scholar Nakamura, S, Kawamoto, Y, Nakano, S, Akiguchi, I, Kimura, J 1998 Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy. J Neuropathol Exp Neurol 57 690 698 PubMed Google Scholar Nakamura, S, Kawamoto, Y, Nakano, S, Akiguchi, I 2000 Expression of the endocytosis regulatory proteins Rab5 and Rabaptin-5 in glial cytoplasmic inclusions from brains with multiple system atrophy. Clin Neuropathol 19 51 56 PubMed Google Scholar Ozawa, T, Okuizumi, K, Ikeuchi, T, Wakabayashi, K, Takahashi, H, Tsuji, S 2001 Analysis of the expression level of alpha-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy. Acta Neuropathol (Berl) 102 188 190 Google Scholar Papp, MI, Kahn, JE, Lantos, PL 1989 Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94 79 100 CrossRef PubMed Google Scholar Piao, YS, Hayashi, S, Hasegawa, M, Wakabayashi, K, Yamada, M, Yoshimoto, M, Ishikawa, A, Iwatsubo, T, Takahashi, H 2001 Co-localization of alpha-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration. Acta Neuropathol (Berl) 101 285 293 Google Scholar Richter-Landsberg, C, Gorath, M, Trojanowski, JQ, Lee, VM 2000 alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62 9 14 CrossRef PubMed Google Scholar Singleton, AB, Farrer, M, Johnson, J, Singleton, A, Hague, S, Kachergus, J, Hulihan, M, Peuralinna, T, Dutra, A, Nussbaum, R, Lincoln, S, Crawley, A, Hanson, M, Maraganore, D, Adler, C, Cookson, MR, Muenter, M, Baptista, M, Miller, D, Blancato, J, Hardy, J, Gwinn-Hardy, K 2003 alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302 841 CrossRef PubMed Google Scholar Solano, SM, Miller, DW, Augood, SJ, Young, AB, Penney, JB, Jr 2000 Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson’s disease. Ann Neurol 47 201 210 CrossRef PubMed Google Scholar Spillantini, MG, Crowther, RA, Jakes, R, Cairns, NJ, Lantos, PL, Goedert, M 1998 Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251 205 208 PubMed Google Scholar Sung, JY, Kim, J, Paik, SR, Park, JH, Ahn, YS, Chung, KC 2001 Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein. J Biol Chem 276 27441 27448 PubMed Google Scholar Wakabayashi, K, Yoshimoto, M, Tsuji, S, Takahashi, H 1998 Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249 180 182 CrossRef PubMed Google Scholar Wenning, GK, Tison, F, Ben Shlomo, Y, Daniel, SE, Quinn, NP 1997 Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 12 133 147 PubMed Google Scholar Yazawa, I, Giasson, BI, Sasaki, R, Zhang, B, Joyce, S, Uryu, K, Trojanowski, JQ, Lee, VM 2005 Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45 847 859 CrossRef PubMed Google Scholar Copyright information
© Springer-Verlag/Wien 2005