Cyclin-dependent kinase 5 phosphorylates and induces the degradation of ataxin-2.
The expansion of a polyQ repeat within the ataxin-2 protein causes spinocerebellar ataxia type 2 (SCA2). However, neither the precise pathological mechanism nor the physiological functions of ataxin-2 are known. Ataxin-2 contains 47 (S/T)P sequences, which are targeted by proline-directed protein kinases such as the cyclin-dependent kinase 5 (Cdk5). We hypothesized that ataxin-2 is phosphorylated by Cdk5. In fact, phosphorylation of ataxin-2 by Cdk5-p25 was shown using two methods: in vitro(32)P labeling and electrophoretic mobility shift on Phos-tag SDS-PAGE. The fractionation of ataxin-2 into three portions, the N-terminal fragment (NF, amino acids 1-507), the middle fragment (MF, amino acids 508-905), and the C-terminal fragment (CF, amino acids 906-1313) showed that NF and MF were phosphorylated slightly and highly, respectively, by Cdk5-p25 when expressed in COS-7 cells. Cdk5-mediated phosphorylation induced the degradation of NF remarkably and MF moderately. Furthermore, toxic ataxin-2-41Q underwent proteasomal degradation after phosphorylation by Cdk5. These results suggest that Cdk5 controls the abundance of both normal and polyQ-expanded ataxin-2 protein in neurons, which implies that Cdk5 activity is a therapeutic approach for SCA2.
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan. Electronic address: a7203ki@tmu.ac.jp.
Akiko
A
Asada
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Rena
R
Yamazaki
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
Yoshihiro
Y
Kino
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Taro
T
Saito
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Taeko
T
Kimura
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
Mao
M
Miyake
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8585, Japan.
Masato
M
Hasegawa
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Bunkyo, Tokyo 113-8421, Japan.
Nobuyuki
N
Nukina
Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan. Electronic address: hisanaga-shinichi@tmu.ac.jp.
Shin-Ichi
S
Hisanaga
D000818:Animals; D000067528:Ataxins; D019556:COS Cells; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation
D000067528:Ataxins; D009419:Nerve Tissue Proteins; D051360:Cyclin-Dependent Kinase 5
Ataxin-2; Cdk5; Phosphorylation; PolyQ; Proteasomal degradation; SCA2