Lysosomal Storage of Subunit c of Mitochondrial ATP Synthase in Brain-Specific Atp13a2-Deficient Mice

Shigeto Sato; Masato Koike; Manabu Funayama; Junji Ezaki; Takahiro Fukuda; Takashi Ueno; Yasuo Uchiyama; Nobutaka Hattori

doi:10.1016/j.ajpath.2016.08.006

Lysosomal Storage of Subunit c of Mitochondrial ATP Synthase in Brain-Specific Atp13a2-Deficient Mice

Am J Pathol. 2016 Dec;186(12):3074-3082. doi: 10.1016/j.ajpath.2016.08.006. Epub 2016 Oct 19.

Authors

Shigeto Sato¹, Masato Koike², Manabu Funayama³, Junji Ezaki⁴, Takahiro Fukuda⁵, Takashi Ueno⁶, Yasuo Uchiyama⁷, Nobutaka Hattori⁸

Affiliations

¹ Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
² Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
³ Research Institute for Disease of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁴ Translational Research Center, Fukushima Medical University, Fukushima, Japan.
⁵ Division of Neuropathology, Department of Neuropathology, The Jikei University School of Medicine, Tokyo, Japan.
⁶ Laboratory of Proteomics and Biomolecular, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁷ Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁸ Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: [email protected].

PMID: 27770614
DOI: 10.1016/j.ajpath.2016.08.006

Abstract

Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of early-onset parkinsonism linked to the PARK9 locus. The causative gene for KRS is Atp13a2, which encodes a lysosomal type 5 P-type ATPase. We recently showed that KRS/PARK9-linked mutations lead to several lysosomal alterations, including reduced proteolytic processing of cathepsin D in vitro. However, it remains unknown how deficiency of Atp13a2 is connected to lysosomal impairments. To address this issue, we analyzed brain tissues of Atp13a2 conditional-knockout mice, which exhibited characteristic features of neuronal ceroid lipofuscinosis, including accumulation of lipofuscin positive for subunit c of mitochondrial ATP synthase, suggesting that a common pathogenic mechanism underlies both neuronal ceroid lipofuscinosis and Parkinson disease.

MeSH terms

Adenosine Triphosphatases / genetics*
Adenosine Triphosphatases / metabolism
Animals
Brain / enzymology
Brain / pathology
Cathepsin D / metabolism
Disease Models, Animal
Female
Gene Knockout Techniques
Humans
Lipofuscin / metabolism
Lysosomes / enzymology
Lysosomes / pathology
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mitochondrial Proton-Translocating ATPases / genetics
Mitochondrial Proton-Translocating ATPases / metabolism*
Mutation
Neuronal Ceroid-Lipofuscinoses / enzymology
Neuronal Ceroid-Lipofuscinoses / genetics
Neuronal Ceroid-Lipofuscinoses / pathology
Organ Specificity
Parkinson Disease / enzymology
Parkinson Disease / genetics*
Parkinson Disease / pathology
Parkinsonian Disorders / enzymology
Parkinsonian Disorders / genetics*
Parkinsonian Disorders / pathology
Proton-Translocating ATPases / genetics*
Proton-Translocating ATPases / metabolism

Substances

ATP13A2 protein, human
Lipofuscin
Membrane Proteins
Cathepsin D
ATP13A2 protein, mouse
Adenosine Triphosphatases
mitochondrial ATPase subunit c
Mitochondrial Proton-Translocating ATPases
Proton-Translocating ATPases

Supplementary concepts

Kufor-Rakeb syndrome