title: Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum.
abstract: 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.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takahashi
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Nozomu
authors.initials: N
authors.lastname: Sato
authors.forename: Masato
authors.initials: M
authors.lastname: Obayashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Niimi
authors.forename: Taro
authors.initials: T
authors.lastname: Ishiguro
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Yamada
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Takeo
authors.initials: T
authors.lastname: Kato
authors.forename: Masaki
authors.initials: M
authors.lastname: Takao
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Mori
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; C579455:BDNF protein, human