Role of Neu4L sialidase and its substrate ganglioside GD3 in neuronal apoptosis induced by catechol metabolites

Hasegawa, Takafumi; Sugeno, Naoto; Takeda, Atsushi; Matsuzaki-Kobayashi, Michiko; Kikuchi, Akio; Furukawa, Katsutoshi; Miyagi, Taeko; Itoyama, Yasuto

doi:10.1016/j.febslet.2006.12.046

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Volume 581, Issue 3 , Pages 406-412, 6 February 2007

Role of Neu4L sialidase and its substrate ganglioside GD3 in neuronal apoptosis induced by catechol metabolites

Edited by Vladimir Skulachev

Takafumi Hasegawa
- Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan
Naoto Sugeno
- Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan
Atsushi Takeda
- Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan
- Corresponding author. Fax: +81 22 717 7189.
Michiko Matsuzaki-Kobayashi
- Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan
Akio Kikuchi
- Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan
Katsutoshi Furukawa
- Department of Geriatric and Complementary Medicine, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan
Taeko Miyagi
- Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan
Yasuto Itoyama
- Department of Neurology, Tohoku University School of Medicine, Sendai, Miyagi 980-8574, Japan

Received 28 July 2006; received in revised form 22 November 2006; accepted 18 December 2006. published online 10 January 2007.

Abstract

Mammalian sialidases are key enzymes in the degradation of glycoconjugates. Neu4L sialidase is localized to mitochondria and specifically expressed in brain. To elucidate the pathophysiological roles of Neu4L in the nervous system, we investigated the possible involvement of Neu4L in the apoptotic neurodegeneration under the existence of catechol metabolites generated by tyrosinase. We demonstrated that: (i) the expression level of Neu4L was dramatically decreased prior to apoptosis; (ii) the apoptotic phenotype was characterized by cytochrome c release into cytosol concomitant with the trafficking of ganglioside GD3 to mitochondria; and (iii) the inhibitor of glucosylceramide synthase partially recovered cell viability. Neu4L and its substrate GD3 may act as key molecules in the mitochondrial apoptotic pathway in neuronal cells.

Keywords: Sialidase, Neu4L, Ganglioside GD3, Mitochondria, Apoptosis, Neuronal death

Abbreviations: DMEM, Dulbecco’s modified eagle’s medium, D-PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, MTT, 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide, Ab, antibody, DA, dopamine, Apaf-1, apoptosis protease activating factor-1, AIF, apoptosis inducing factor