トレハロースによる Akt 発現量低下とそのメカニズムに関する研究

概要


༤ኈㄽᩥ

ࢺࣞࣁ࣮ࣟࢫ࡟ࡼࡿ Akt Ⓨ⌧㔞పୗ࡜
ࡑࡢ࣓࢝ࢽࢬ࣒࡟㛵ࡍࡿ◊✲

ᗈᓥ኱Ꮫ኱Ꮫ㝔་ṑ⸆ಖ೺Ꮫ◊✲⛉
༤ኈㄢ⛬་ṑ⸆Ꮫᑓᨷ
⏕యᶵ⬟ศᏊືែᏛ◊✲ᐊ
ᖹᡂ 28 ᖺᗘධᏛ   ᱵ⏣ 㤶ⱑ
୺ᣦᑟᩍဨ    ྂṊ ᘺ୍㑻




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┠ḟ
␎ㄒ                             



4

➨ 1 ❶ ᗎㄽ                         



5

➨ 2 ❶ ࢺࣞࣁ࣮ࣟࢫࡀ ALP 㛵㐃ࢱࣥࣃࢡ㉁ࡢ⣽⬊ෆᒁᅾཬࡧⓎ⌧
㔞࡟ཬࡰࡍᙳ㡪
➨ 1 ⠇ ⥴ゝ                          

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➨ 2 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀ TFEB ࡢ⣽⬊ෆᒁᅾ࡟ཬࡰࡍᙳ㡪      

12

➨ 3 ⠇ࢺࣞࣁ࣮ࣟࢫࡀ LC3-II ཬࡧ p62 ࡢࢱࣥࣃࢡ㉁Ⓨ⌧㔞࡟ཬࡰࡍ
ᙳ㡪                          
➨  ⠇ ᑠᣓ                          

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16

➨ 3 ❶ ࢺࣞࣁ࣮ࣟࢫࡀ Akt ࡢࢱࣥࣃࢡ㉁ཬࡧ mRNA Ⓨ⌧㔞࡟ཬࡰ
ࡍᙳ㡪
➨ 1 ⠇ ⥴ゝ                          

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➨ 2 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀࣜࣥ㓟໬ Akt ཬࡧ⥲ Akt ࡢࢱࣥࣃࢡ㉁Ⓨ⌧㔞࡟
ཬࡰࡍᙳ㡪                       

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➨ 3 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀ Akt ࢔࢖ࢯࣇ࢛࣮࣒ࡢࢱࣥࣃࢡ㉁Ⓨ⌧࡟ཬࡰࡍ
ᙳ㡪                         

20

➨ 4 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀ Akt ࢔࢖ࢯࣇ࢛࣮࣒ࡢ mRNA Ⓨ⌧㔞࡟ཬࡰࡍ
ᙳ㡪                          
➨ 5 ⠇ ᑠᣓ                          

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24

➨ 4 ❶ ࢺࣞࣁ࣮ࣟࢫࡀ⣽⬊ෆࢩࢢࢼࣝఏ㐩⤒㊰࡟ཬࡰࡍᙳ㡪ࡢ⥙⨶
ⓗゎᯒ
➨ 1 ⠇ ⥴ゝ                          

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➨ 2 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀ✀ࠎࡢࢱࣥࣃࢡ㉁ࡢࣜࣥ㓟໬ࣞ࣋ࣝ࡟ཬࡰࡍ
ᙳ㡪                          

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➨  ⠇ ᑠᣓ                          

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➨ 5 ❶ ࢺࣞࣁ࣮ࣟࢫࡀ c-Jun/JunB ࡢࢱࣥࣃࢡ㉁Ⓨ⌧㔞࡟ཬࡰࡍ


ᙳ㡪
➨ 1 ⠇ ⥴ゝ                          

2

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➨ 2 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀࣜࣥ㓟໬ c-Jun ཬࡧ⥲ c-Jun ࡢࢱࣥࣃࢡ㉁Ⓨ⌧㔞
࡟ཬࡰࡍᙳ㡪                      

34

➨ 3 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀࣜࣥ㓟໬ JNK ཬࡧ⥲ JNK ࡢࢱࣥࣃࢡ㉁Ⓨ⌧㔞
࡟ཬࡰࡍᙳ㡪                      

36

➨ 4 ⠇ ࢺࣞࣁ࣮ࣟࢫࡀࣜࣥ㓟໬ JunB ཬࡧ⥲ JunB ࡢࢱࣥࣃࢡ㉁Ⓨ⌧㔞
࡟ཬࡰࡍᙳ㡪                      

38

➨ 5 ⠇ ࣉࣟࢸ࢔ࢯ࣮࣒㜼ᐖ๣ࡀࢺࣞࣁ࣮ࣟࢫ࡟ࡼࡿ c-Jun/JunB ࢱࣥࣃ
ࢡ㉁Ⓨ⌧㔞పୗ࡟ཬࡰࡍᙳ㡪               

40

➨ 6 ⠇ ᑠᣓ                          

42

➨ 6 ❶ࢺࣞࣁ࣮ࣟࢫ࡟ࡼࡿ Akt Ⓨ⌧㔞పୗ࡜ c-Jun/JunB Ⓨ⌧㔞పୗ
ࡢ㛵㐃ᛶࡢ᳨ウ
➨ 1 ⠇ ⥴ゝ                          
➨ 2 ⠇ ࣉࣟࢸ࢔ࢯ࣮࣒㜼ᐖ๣ࡀࢺࣞࣁ࣮ࣟࢫ࡟ࡼࡿ AKT1 mRNA Ⓨ⌧
㔞పୗ࡟ཬࡰࡍᙳ㡪                   
➨3⠇

c-Jun/JunB 㐣๫Ⓨ⌧ࡀࢺࣞࣁ࣮ࣟࢫ࡟ࡼࡿ Akt Ⓨ⌧㔞పୗཬࡧ
LC3-II Ⓨ⌧㔞ቑຍ࡟ཬࡰࡍᙳ㡪             

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44
45
47

➨ 4 ⠇ ᑠᣓ

➨  ❶ ⥲ᣓཬࡧ⪃ᐹ                     

 48

ᐇ㦂ࡢ㒊                           

52

ᘬ⏝ᩥ
ᩥ⊩                           

 67

ᮏㄽᩥ࡟㛵㐃ࡋࡓᏛ఍Ⓨ⾲                   

73

ㅰ㎡
                                74

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␎ㄒ

ALP, autophagy lysosomal pathway
AP-1, activator protein 1
AMPK, AMP-activated protein kinase
CLEAR, coordinated lysosomal expression and regulation
CMA, chaperon-mediated autophagy
DAPI, 4’6-diamidino-2-phenylindole
DMEM, Dulbecco’s modified Esgle’s medium
DMSO, dimethyl sulfoxide
HA, human influenza hemagglutinin
JNK, c-Jun N-terminal kinase
LC3, microtubule-associated protein 1 light chain 3
MPP+, 1-methyl-4-phenyl-pyridinium ion
mTOR, mammalian target of rapamycin
mTORC1, mammalian target of rapamycin complex 1
D-PBS, Dulbecco’s phosphate-buffered saline
PD, Parkinson’s disease
PVDF, polyvinylidene difluoride
qRT-PCR, quantitative real-time reverse transcription PCR
S.D., standard deviation
SDS, sodium dodecyl sulfate
SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis
SLC2A, solute carrier 2A
SQSTM1, sequestosome-1
TBS, tris buffered saline
TFEB, transcription factor EB
ULK1, unc-51-like kinase-1




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➨ 1 ❶ ᗎㄽ
 ࣮࢜ࢺࣇ࢓ࢪ࣮ࡣࠊ⮬㣗స⏝࡜ࡶ࿧ࡤࢀࡿࣜࢯࢯ࣮࣒ࢆ௓ࡋࡓ኱つᶍ࡞⣽⬊ෆศゎᶵ
ᵓ࡛࠶ࡾࠊ࣐ࢡ࣮ࣟ࢜ࢺࣇ࢓ࢪ࣮ࠊ࣑ࢡ࣮ࣟ࢜ࢺࣇ࢓ࢪ࣮ࠊࢩࣕ࣌ࣟࣥ௓ᅾᛶ࣮࢜ࢺࣇ
࢓ࢪ࣮㸦chaperon-mediated autophagy: CMA㸧࡟༊ูࡉࢀࡿ㸦Parzych and Klionsky, 2014㸧
ࠋ
࣐ࢡ࣮ࣟ࢜ࢺࣇ࢓ࢪ࣮ࡢ㐣⛬࡟࠾࠸࡚ࠊ㝸㞳⭷࡟ࡼࡗ࡚ྲྀࡾᅖࡲࢀࡓ⣽⬊ෆᡂศࡣࠊ࢜
࣮ࢺࣇ࢓ࢦࢯ࣮࣒࡜࿧ࡤࢀࡿ஧
㔜⭷ᵓ㐀య࡟㝸㞳ࡉࢀࡿ㸦Fig.

Cytoplasm
Lysosomal
hydrolase

1㸧ࠋ࣮࢜ࢺࣇ࢓ࢦࢯ࣮࣒ࡣࣜࢯ

Lysosome

ࢯ࣮࣒࡜⼥ྜࡋ࡚࣮࢜ࢺࣜࢯࢯ
࣮࣒ࢆᙧᡂࡋࠊ࣮࢜ࢺࣇ࢓ࢦࢯ
࣮࣒ࡢෆᐜ≀ࡣࣜࢯࢯ࣮࣒ෆຍ

Isolation
membrane

Ỉศゎ㓝⣲࡟ࡼࡗ࡚኱つᶍ࡟ศ

Autophagosome

Autolysosome

Fig. 1 Schematic diagram of autophagy

ゎࡉࢀࡿ㸦Fig. 1㸧
ࠋ࣑ࢡ࣮ࣟ࢜ࢺ
ࣇ࢓ࢪ࣮࡟࠾࠸࡚ࠊ⣽⬊ෆᡂศࡣ࣮࢜ࢺࣇ࢓ࢦࢯ࣮࣒ࢆᙧᡂࡏࡎࠊࣜࢯࢯ࣮࣒࡟┤᥋ྲྀ
ࡾ㎸ࡲࢀࡿࠋࡲࡓࠊCMA ࡢ㐣⛬࡟࠾࠸࡚ࠊKFERQ 㓄ิࢆᣢࡘࢱࣥࣃࢡ㉁ࡣࠊheat-shock
70 kDa protein 8 ࡟ࡼࡗ࡚ㄆ㆑ࡉࢀࠊlysosomal-associated membrane protein type 2A ࢆ௓ࡋ
࡚㑅ᢥⓗ࡟ࣜࢯࢯ࣮࣒࡟ᑟ࠿ࢀࡿࠋ୍⯡ⓗ࡟࣮࢜ࢺࣇ࢓ࢪ࣮࡜࿧ࡤࢀࡿࡢࡣ࣐ࢡ࣮ࣟ࢜
ࢺࣇ࢓ࢪ࣮ࡢࡇ࡜࡛࠶ࡾࠊᮏ◊✲࡟࠾ࡅࡿ࣮࢜ࢺࣇ࢓ࢪ࣮ࡲࡓࡣ࣮࢜ࢺࣇ࢓ࢪ࣮࣭ࣜࢯ
ࢯ࣮࣒⤒㊰㸦autophagy-lysosomal pathway: ALP㸧࡜࠸࠺グ㏙ࡣࠊ୺࡟࣐ࢡ࣮ࣟ࢜ࢺࣇ࢓
ࢪ࣮ࡢࡇ࡜ࢆᣦࡍࠋ
㏆ᖺࠊALP ࡢᶵ⬟␗ᖖࡀᵝࠎ࡞⑌ᝈࡢⓎ⑕࡟ࡘ࡞ࡀࡿྍ⬟ᛶࡀᣦ᦬ࡉࢀ࡚࠸ࡿࠋ≉
࡟ࠊ2006 ᖺ࡟ࠊ⬻≉␗ⓗ࣮࢜ࢺࣇ࢓ࢪ࣮Ḟᦆ࣐࢘ࢫࡀ⚄⤒ኚᛶ⑌ᝈ≉᭷ࡢࢱࣥࣃࢡ㉁
จ 㞟 య⵳ ✚ࢆ క࠺ ⚄⤒⣽ ⬊ Ṛཬ ࡧ⚄ ⤒ኚ ᛶ⑌ᝈ ᵝ ⑕≧ ࢆᘬ ࡁ㉳ ࡇࡍࡇ ࡜ ࡀሗ ࿌
㸦Komatsu et al., 2006; Hara et al., 2006㸧ࡉࢀ࡚௨᮶ࠊALP ࡢᶵ⬟␗ᖖࡀᵝࠎ࡞⚄⤒ኚᛶ
⑌ᝈࡢⓎ⑕࡟㛵୚ࡍࡿドᣐࡀ⵳✚ࡋ࡚ࡁ࡚࠸ࡿࠋࣃ࣮࢟ࣥࢯࣥ⑓㸦Parkinson’s disease: PD㸧
ࡣࠊ࢔ࣝࢶࣁ࢖࣐࣮⑓࡟ḟ࠸࡛ 2 ␒┠࡟㢖ᗘࡢ㧗࠸⚄⤒ኚᛶ⑌ᝈ࡛࠶ࡾࠊ୰⬻ࡢ㯮㉁࡟
࠾ࡅࡿࢻࣃ࣑ࣥ⚄⤒ࡢ㑅ᢥⓗ⬺ⴠཬࡧṧᏑ⚄⤒⣽⬊࡟࠾ࡅࡿࣞࣅ࣮ᑠయ࡜࿧ࡤࢀࡿࢱ
ࣥࣃࢡ㉁จ㞟యࡢ⵳✚ࢆ⑓⌮Ꮫⓗ≉ᚩ࡜ࡍࡿ㸦de Lau and Breteler, 2006; Kalia and Lang,
2015㸧
ࠋ⌧ᅾࡲ࡛࡟ࠊPD ᝈ⪅ࡢṚᚋ⬻࡟࠾࠸࡚ࠊ࣮࢜ࢺࣇ࢓ࢪ࣮㛵㐃✵⬊ࡢ⵳✚ࡸ ALP

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㛵㐃ࢱࣥࣃࢡ㉁ࡢⓎ⌧㔞ኚ໬ࡀㄆࡵࡽࢀࡿࡇ࡜㸦Anglade et al., 1997; Toulorge et al., 2016;
Moors et al., 2017㸧
ࠊALP 㛵㐃ࢱࣥࣃࢡ㉁ࡣࣞࣅ࣮ᑠయࡢᵓᡂᡂศ࡛࠶ࡿࡇ࡜ࡀሗ࿌ࡉࢀ
࡚࠸ࡿ㸦Decressac et al., 2013; Arotcarena et al., 2019㸧
ࠋࡲࡓࠊPD ᝈ⪅ࡢ⣙ 5%ࢆ༨ࡵࡿ㑇
ఏᛶ PD ࡢཎᅉ㑇ఏᏊࡢ࠸ࡃࡘ࠿ࡣࠊALP ᶵ⬟࡟㔜せ࡞ᙺ๭ࢆᯝࡓࡍࢱࣥࣃࢡ㉁ࢆࢥ࣮
ࢻࡋ࡚࠸ࡿ㸦Moors et al., 2017; Senkevich and Gan-Or, 2019㸧
ࠋࡉࡽ࡟ࠊࢻࣃ࣑ࣥ⚄⤒㑅ᢥ
ⓗ࣮࢜ࢺࣇ࢓ࢪ࣮Ḟᦆ࣐࢘ࢫࡣࠊ⪁㱋ᮇ࡟࠾࠸࡚ࣞࣅ࣮ᑠయᵝᑒධయࡢ⵳✚ࡸ㐠ືᶵ⬟
㞀ᐖࢆᘬࡁ㉳ࡇࡍࡇ࡜ࡶ᫂ࡽ࠿࡟࡞ࡗ࡚࠸ࡿ㸦Ahmed et al., 2012; Friedman et al., 2012;
Sato et al., 2018㸧
ࠋᙜ◊✲ࢢ࣮ࣝࣉ࡟࠾࠸࡚ࡶࠊPD 㛵㐃໬Ꮫ≀㉁࡛࠶ࡿ 1-methyl-4-phenylpyridinium ion 㸦MPP+㸧ཬࡧࣟࢸࣀࣥࡀప⃰ᗘ࡟࠾࠸࡚ࣜࢯࢯ࣮࣒ᶵ⬟పୗࢆᘬࡁ㉳ࡇ
ࡋࠊALP ࢆ㜼ᐖࡍࡿࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋ࡚ࡁࡓ㸦Miyara et al., 2016; Sakamoto et al., 2016㸧
ࠋ
ୖグࢆྵࡴᩘከࡃࡢ◊✲ࡼࡾࠊALP ᶵ⬟ࢆஹ㐍ࡍࡿ≀㉁ࡢ᥈⣴ࡸࡑࡢ࣓࢝ࢽࢬ࣒ゎ᫂
ࡣ PD ࢆྵࡴ ALP 㛵㐃⑌ᝈࡢ἞⒪ᡓ␎㛤Ⓨࢆ㐍ࡵࡿୖ࡛㔜せ࡛࠶ࡿ࡜⪃࠼ࡽࢀࡿࠋ
ࢺࣞࣁ࣮ࣟࢫࡣࠊࢢࣝࢥ࣮ࢫ 2 ศᏊࡀD,D-1,1 ⤖ྜࡋ
ࡓ㠀㑏ඖᛶ஧⢾㢮㸦Fig. 2㸧࡛࠶ࡾࠊ⣽⳦ࠊ㓝ẕࠊ⳦㢮ࠊ
᪻⹸ࠊ↓⬨᳝ື≀ࠊ᳜≀࡞࡝ࠊ⮬↛⏺࡟ᗈࡃᏑᅾࡍࡿ

glucose

㸦Lee et al., 2018㸧
ࠋࡇࢀࡽࡢ⏕≀࡟࠾࠸࡚ࠊࢺࣞࣁ࣮ࣟ
ࢫࡣࠊᴟ㝈 ᗘࠊᰤ㣴㣚㣹ࠊᾐ㏱ᅽࢫࢺࣞࢫࠊ஝⇱࡞࡝
ࡢᵝࠎ࡞⎔ቃࢫࢺࣞࢫ࡟ᛂ⟅ࡋ࡚⣽⬊ෆ࡟⵳✚ࡋࠊࢱ
ࣥࣃࢡ㉁ࡸ⏕య⭷ࢆಖㆤࡍࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿࠋࡲ

glucose
Fig. 2 Structure of trehalose

ࡓࠊࢺࣞࣁ࣮ࣟࢫࡣࠊ᪻⹸ࡢ୺せ࡞⾑⢾࡛࠶ࡾࠊ㣕⩧ࡢ࢚ࢿࣝࢠ࣮※࡜ࡋ࡚฼⏝ࡉࢀ࡚
࠸ࡿ㸦Elbein, 1974㸧ࠋࢹࣥࣉࣥࢆ⏝࠸࡚ࢺࣞࣁ࣮ࣟࢫࡢ኱㔞⏕⏘ࡀྍ⬟࡜࡞ࡗࡓ⌧௦࡟
࠾࠸࡚ࠊࢺࣞࣁ࣮ࣟࢫࡣࡑࡢ≉ᚩⓗ࡞≀ᛶ࠿ࡽ㣗ရࡸ໬⢝ရ➼࡟ᖜᗈࡃ฼⏝ࡉࢀ࡚࠸ࡿ
㸦TREHA‫ ט‬web; HAYASHIBARA㸧ࠋࣄࢺࡣయෆ࡛ࢺࣞࣁ࣮ࣟࢫࢆྜᡂࡍࡿࡇ࡜ࡣฟ᮶
࡞࠸ࡀࠊ㣗ရࢆ㏻ࡌ࡚ᑡ㔞ࡢࢺࣞࣁ࣮ࣟࢫࢆ᪥ᖖⓗ࡟ᦤྲྀࡋ࡚࠾ࡾࠊయෆ࡟ྲྀࡾ㎸ࡲࢀ
ࡓࢺࣞࣁ࣮ࣟࢫࡢከࡃࡣࠊ୺࡟ᑠ⭠ࡢๅᏊ⦕⭷࡟Ⓨ⌧ࡍࡿࢺࣞࣁ࣮ࣛࢮ࡟ࡼࡗ࡚ࢢࣝࢥ
࣮ࢫ 2 ศᏊ࡟ศゎࡉࢀࡿ㸦Ishihara et al., 1997㸧ࠋ
mammalian target of rapamycin㸦mTOR㸧ࡣࠊ࣮࢜ࢺࣇ࢓ࢪ࣮ࡢ㛤ጞࢆไᚚࡍࡿ୺せ࡞
ᅉᏊ࡛࠶ࡾࠊ⣽⬊ෆࡢᰤ㣴㣚㣹≧ែࡸ rapamycin ࡞࡝ࡢ ALP ㄏᑟ๣ࡣࠊmTOR ࡢάᛶప
ୗࢆ௓ࡋ࡚࣮࢜ࢺࣇ࢓ࢪ࣮ࢆㄏᑟࡍࡿࠋ2007 ᖺ࡟ Sarkar ࡽࡣࠊࢺࣞࣁ࣮ࣟࢫࡀ㧗⃰ᗘ
㸦100 mM㸧࡟࠾࠸࡚ࠊmTOR 㠀౫Ꮡⓗ࡟ ALP ᶵ⬟ࢆஹ㐍ࡍࡿࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓ㸦Table
1, Sarkar et al., 2007㸧ࠋࡲࡓࠊ༢⢾㸦ࣇࣝࢡࢺ࣮ࢫࡸࢯࣝࣅࢺ࣮ࣝ࡞࡝㸧ࡸࠊ㑏ඖᛶከ⢾

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Table 1 Several mechanisms of trehalose-induced ALP activation.

㢮㸦࣐ࣝࢺ࣮ࢫ࡞࡝㸧࡛ࡣ ALP ᶵ⬟ஹ㐍ࡣᘬࡁ㉳ࡇࡉࢀ࡞࠸ࡇ࡜࠿ࡽࠊࢺࣞࣁ࣮ࣟࢫ
࡟ࡼࡿ ALP ᶵ⬟ஹ㐍ࡣࠊ༢࡟ᾐ㏱ᅽࢫࢺࣞࢫ࡟ࡼࡿࡶࡢ࡛ࡣ࡞ࡃࠊ㠀㑏ඖᛶከ⢾㢮࡟
≉ᚩⓗ࡞స⏝࡛࠶ࡿࡇ࡜ࡀ♧၀ࡉࢀ࡚࠸ࡿ㸦Higuchi et al., 2015; Yoon et al., 2017㸧
ࠋ
 ᐇ㝿࡟ࠊࢺࣞࣁ࣮ࣟࢫࡣ ALP ᶵ⬟ஹ㐍ࢆ௓ࡋ࡚⚄⤒ኚᛶ⑌ᝈ࡞࡝ࡢࣔࢹࣝື≀ࡢ⑌
ᝈ⑕≧ࢆ⦆࿴ࡍࡿࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡾࡘࡘ࠶ࡿ㸦Hosseinpour-Moghaddam et al., 2018㸧ࠋ
౛࠼ࡤࠊࢺࣞࣁ࣮ࣟࢫ㸦3%㣧Ỉ 48 ᫬㛫ᢞ୚㸧ࡣࠊ㠀࢔ࣝࢥ࣮ࣝᛶ⬡⫫ᛶ⫢⑌ᝈࣔࢹࣝ
࣐࢘ࢫ࡟࠾ࡅࡿ⫢⮚୰⬡⫫⵳✚ࢆᢚไࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ㸦Table 1; DeBosch et
al., 2016䠅ࠋࡲࡓࠊࢺࣞࣁ࣮ࣟࢫ㸦2%㣧Ỉ 18㹼24 ࣨ᭶ᢞ୚㸧ࡣࠊࣜࢯࢯ࣮࣒⑓㸦ⱝᖺᛶࢭ
ࣟ࢖ࢻ࣏ࣜࣇࢫࢳࣥ⑕㸧ࣔࢹ࣐ࣝ࢘ࢫ࡟࠾ࡅࡿ⬻㔜㔞పୗࢆᢚไࡋࠊ⏕Ꮡᮇ㛫ࢆ⣙ 150 ᪥
ᘏ㛗ࡉࡏࡿࡇ࡜ࡶሗ࿌ࡉࢀ࡚࠸ࡿ㸦Table1; Palmieri et al., 2017㸧
ࠋࡇࢀࡽࡢሗ࿌࡟࠾࠸࡚ࠊ
ࢺࣞࣁ࣮ࣟࢫࡢຠᯝࡣ ALP ᶵ⬟ஹ㐍ࢆ௓ࡋ࡚ᘬࡁ㉳ࡇࡉࢀࡿࡇ࡜ࡀ♧၀ࡉࢀ࡚࠸ࡿࠋ
⣽⬊ࢆ⏝࠸ࡓᐇ㦂⣔࡟࠾࠸࡚ࡶࠊࢺࣞࣁ࣮ࣟࢫࡣࠊࣁࣥࢳࣥࢺࣥ⑓㛵㐃ኚ␗ᆺ huntingtin
ཬࡧ PD 㛵㐃ኚ␗ᆺD-synuclein ࡢ࣮࢜ࢺࣇ࢓ࢪ࣮ศゎࢆಁ㐍ࡋࠊࡑࡢẘᛶࢆ㍍ῶࡍࡿࡇ
࡜㸦Sarkar et al., 2007㸧
ࠊMPP+ཬࡧࣟࢸࣀࣥ࡟ࡼࡿࣜࢯࢯ࣮࣒⭷◚ቯཬࡧ ALP ᶵ⬟పୗ
ࢆᢚไࡋࠊࡑࡢẘᛶࢆ㍍ῶࡍࡿࡇ࡜㸦Dehay et al., 2010; Wu et al., 2015㸧࡞࡝ࡀሗ࿌ࡉࢀ
࡚࠸ࡿࠋᙜ◊✲ᐊ࡟࠾࠸࡚ࡶࠊࢺࣞࣁ࣮ࣟࢫࡀప⃰ᗘ MPP+࡟ࡼࡿ ALP ᶵ⬟పୗཬࡧ⣽
⬊Ṛࢆ୍㒊㍍ῶࡍࡿࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋ࡚ࡁࡓ㸦Miyara et al., 2016㸧
ࠋ

7

ࢺࣞࣁ࣮ࣟࢫ࡟ࡼࡿ ALP ᶵ⬟ஹ㐍࣓࢝ࢽࢬ࣒࡟ࡘ࠸࡚ࡶࠊᵝࠎ࡞⣽⬊ࢆ⏝࠸ࡓᐇ㦂
⣔࡟࠾࠸࡚◊✲ࡀ࡞ࡉࢀ࡚ࡁࡓࠋAMP-activated protein kinase㸦AMPK㸧ࡣࠊ⣽⬊ෆࢢࣝ
ࢥ࣮ࢫ⃰ᗘపୗ࡟క࠺ AMP/ATP ẚࡢቑຍ࡟ᛂ⟅ࡋ࡚άᛶ໬ࡋࠊALP ࡢึᮇẁ㝵࡟࠾࠸
࡚㔜せ࡞ᙺ๭ࢆᢸ࠺ unc-51-like kinase-1㸦ULK1㸧ࡢࣜࣥ㓟໬ࢆ௓ࡋ࡚ ALP ࢆㄏᑟࡍࡿ
ࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿ㸦Kim et al., 2011㸧
ࠋDeBosch ࡽ㸦2016㸧ࡣࠊࢺࣞࣁ࣮ࣟࢫࡀࠊࢢࣝ
ࢥ࣮ࢫࢺࣛࣥࢫ࣏࣮ࢱ࣮ࡢ୍ࡘ࡛࠶ࡿ solute carrier 2A㸦SLC2A㸧ࢆ㜼ᐖࡋࠊ⣽⬊ෆࡢప
ࢢࣝࢥ࣮ࢫ≧ែࢆᘬࡁ㉳ࡇࡍࡇ࡜࡛ࠊAMPK ࡢάᛶ໬ཬࡧ ULK1 ࡢࣜࣥ㓟໬ࢆ௓ࡋ࡚
ALP ᶵ⬟ஹ㐍ࢆᘬࡁ㉳ࡇࡍࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓ㸦Table 1㸧
ࠋ୍᪉ࠊ2009 ᖺ࡟㌿෗ᅉᏊ
transcription factor EB㸦TFEB㸧ࡀ ALP 㛵㐃㑇ఏᏊࡢ࣐ࢫࢱ࣮ࣞࢠ࣮ࣗࣞࢱ࣮࡛࠶ࡿࡇ࡜
ࡀ᫂ࡽ࠿࡟࡞ࡾ㸦Sardiello et al., 2009㸧
ࠊDehay ࡽ㸦2010㸧ࡣࠊࢺࣞࣁ࣮ࣟࢫࡀ TFEB ࡢ
άᛶ໬㸦᰾⛣⾜㸧ࢆ௓ࡋ࡚ ALP ᶵ⬟ஹ
㐍ࢆᘬࡁ㉳ࡇࡍࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓࠋ
TFEB ࡣࠊ㏻ᖖࠊmammalian target of
rapamycin complex 1㸦mTORC1㸧ࢆጞࡵ
࡜ࡍࡿᵝࠎ࡞࢟ࢼ࣮ࢮ࡟ࡼࡿࣜࣥ㓟໬
ࢆཷࡅࠊ⣽⬊㉁࡟ᒁᅾࡋ࡚࠸ࡿࠋ୍᪉ࠊ
ࣜࢯࢯ࣮࣒ෆࢱࣥࣃࢡ㉁ศゎάᛶࡢప
ୗࡀࢩࢢࢼࣝ࡜࡞ࡾ mTORC1 ࡀࣜࢯ

Fig. 3 A regulation of autophagy-lysosomal gene
expression.

ࢯ࣮࣒⭷࠿ࡽゎ㞳㸦୙άᛶ໬㸧ࡍࡿ࡜ࠊ
Calcineurin ࡟ࡼࡿ⬺ࣜࣥ㓟໬ࡀඃ఩࡜࡞ࡾ TFEB ࡣ᰾࡟⛣⾜ࡍࡿࠋ᰾࡟⛣⾜ࡋࡓ TFEB
ࡣࠊࣜࢯࢯ࣮࣒㑇ఏᏊࡢࣉ࣮ࣟࣔࢱ࣮㡿ᇦ࡟Ꮡᅾࡍࡿ coordinated lysosomal expression
and regulation㸦CLEAR㸧㓄ิ࡟⤖ྜࡋࠊALP 㛵㐃㑇ఏᏊࡢⓎ⌧ࢆಁ㐍ࡍࡿ 㸦Fig. 3,
Settembre et al., 2012; Medina et al., 2015; Napolitano and Ballabio, 2016㸧
ࠋPalmieri㸦2017㸧
ࡽࡣ㏆ᖺࠊ
Akt ࡶࡲࡓ TFEB ࡢ
ࣜࣥ㓟໬㸦Ser 467㸧ࢆᢸ࠺ࡇ
࡜ࢆぢฟࡋࡓࠋࡲࡓࠊࢺࣞࣁ
࣮ࣟࢫࡣࠊࣜࣥ㓟໬ Akt Ⓨ⌧
㔞పୗࢆ௓ࡋ࡚ TFEB ࢆ᰾࡟
⛣⾜ࡉࡏࠊALP 㛵㐃㑇ఏᏊࡢ
Ⓨ⌧ࢆಁ㐍ࡍࡿࡇ࡜ࢆ᫂ࡽ࠿
࡟ࡋࡓ㸦Table 1 and Fig. 4㸧
ࠋ

Fig. 4 A mechanism of trehalose-induced ALP activation proposed
by Palmieri et al. ...

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