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Reduced brain‐derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF‐immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum
Author(s) -
Takahashi Makoto,
Ishikawa Kinya,
Sato Nozomu,
Obayashi Masato,
Niimi Yusuke,
Ishiguro Taro,
Yamada Mitsunori,
Toyoshima Yasuko,
Takahashi Hitoshi,
Kato Takeo,
Takao Masaki,
Murayama Shigeo,
Mori Osamu,
Eishi Yoshinobu,
Mizusawa Hidehiro
Publication year - 2012
Publication title -
neuropathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.701
H-Index - 61
eISSN - 1440-1789
pISSN - 0919-6544
DOI - 10.1111/j.1440-1789.2012.01302.x
Subject(s) - brain derived neurotrophic factor , cerebellum , spinocerebellar ataxia , neuroscience , neurotrophic factors , messenger rna , cerebellar ataxia , medicine , ataxia , biology , receptor , gene , genetics
Spinocerebellar ataxia type 6 (SCA6) is an autosomal‐dominant neurodegenerative disorder caused by a small expansion of tri‐nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α 1A voltage‐dependent calcium channel (Ca v 2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75‐kDa carboxy‐terminal fragment (CTF) of Ca v 2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain‐derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT‐PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum ( n = 3) compared to controls ( n = 6) (Mann–Whitney U ‐test, P = 0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF‐immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF‐immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2‐positive Ca v 2.1 aggregates existed more proximally than the BDNF‐positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Ca v 2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.