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Singh F, Ganley IG. Parkinson's disease and mitophagy: an emerging role for LRRK2. Biochem Soc Trans. 2021;49(2):551-562doi: 10.1042/BST20190236.
Singh, F., & Ganley, I. G. (2021). Parkinson's disease and mitophagy: an emerging role for LRRK2. Biochemical Society transactions, 49(2), 551-562. https://doi.org/10.1042/BST20190236
Singh, Francois, and Ganley, Ian G. "Parkinson's disease and mitophagy: an emerging role for LRRK2." Biochemical Society transactions vol. 49,2 (2021): 551-562. doi: https://doi.org/10.1042/BST20190236
Singh F, Ganley IG. Parkinson's disease and mitophagy: an emerging role for LRRK2. Biochem Soc Trans. 2021 Apr 30;49(2):551-562. doi: 10.1042/BST20190236. PMID: 33769432; PMCID: PMC8106497.
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Biochem Soc Trans. 2021 Apr 30;49(2):551-562. doi: 10.1042/BST20190236.

Parkinson's disease and mitophagy: an emerging role for LRRK2.

Biochemical Society transactions

Francois Singh, Ian G Ganley

Affiliations

  1. MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee DD1 5EH, U.K.

PMID: 33769432 PMCID: PMC8106497 DOI: 10.1042/BST20190236

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress - so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

© 2021 The Author(s).

Keywords: Parkinsons disease; autophagy; leucine-rich repeat kinase; mitophagy

References

  1. Neurobiol Dis. 2020 Nov;145:105056 - PubMed
  2. Neurosci Lett. 2019 Jul 13;705:7-13 - PubMed
  3. Hum Mol Genet. 2019 Aug 15;28(16):2696-2710 - PubMed
  4. Am J Hum Genet. 2016 Mar 3;98(3):500-513 - PubMed
  5. EMBO J. 2017 Jun 14;36(12):1688-1706 - PubMed
  6. EMBO J. 2014 Feb 18;33(4):282-95 - PubMed
  7. Front Neurol. 2017 Oct 04;8:527 - PubMed
  8. Nat Commun. 2017 Mar 09;8:14697 - PubMed
  9. J Cell Biol. 2010 Apr 19;189(2):211-21 - PubMed
  10. Biochem Soc Trans. 2012 Oct;40(5):1134-9 - PubMed
  11. Oxid Med Cell Longev. 2013;2013:683920 - PubMed
  12. Hum Mol Genet. 2012 Feb 15;21(4):890-9 - PubMed
  13. iScience. 2020 Dec 31;24(1):102029 - PubMed
  14. Autophagy. 2010 Oct;6(7):871-8 - PubMed
  15. Adv Exp Med Biol. 2017;1037:89-95 - PubMed
  16. Cell Metab. 2018 Feb 6;27(2):439-449.e5 - PubMed
  17. PLoS One. 2010 Feb 23;5(2):e9367 - PubMed
  18. Nature. 2014 Jun 5;510(7503):162-6 - PubMed
  19. Open Biol. 2018 Nov 7;8(11): - PubMed
  20. Cell Stress. 2020 Mar 04;4(5):99-113 - PubMed
  21. J Neuropsychiatry Clin Neurosci. 2002 Spring;14(2):223-36; discussion 222 - PubMed
  22. J Cell Biol. 2016 Aug 1;214(3):333-45 - PubMed
  23. Mov Disord. 2021 Mar;36(3):704-715 - PubMed
  24. Science. 2013 Apr 19;340(6130):350-3 - PubMed
  25. Autophagy. 2019 Jul;15(7):1296-1308 - PubMed
  26. Hum Mol Genet. 2011 Jan 1;20(1):40-50 - PubMed
  27. J Neurochem. 2016 Oct;139 Suppl 1:77-90 - PubMed
  28. Acta Neuropathol. 2018 Oct;136(4):607-620 - PubMed
  29. Acta Neuropathol Commun. 2019 Mar 14;7(1):41 - PubMed
  30. Sci Rep. 2017 Oct 9;7(1):12816 - PubMed
  31. Neurobiol Dis. 2018 Jan;109(Pt B):249-257 - PubMed
  32. BMC Neurol. 2008 Mar 28;8:6 - PubMed
  33. J Inherit Metab Dis. 2010 Apr;33(2):167-73 - PubMed
  34. J Cell Biol. 2018 Oct 1;217(10):3625-3639 - PubMed
  35. EMBO J. 2018 Jun 15;37(12): - PubMed
  36. Mol Neurodegener. 2019 Aug 29;14(1):36 - PubMed
  37. Nat Neurosci. 2013 Sep;16(9):1257-65 - PubMed
  38. Elife. 2016 Jan 29;5: - PubMed
  39. Trends Biochem Sci. 2015 Apr;40(4):200-10 - PubMed
  40. Neurobiol Dis. 2018 Mar;111:26-35 - PubMed
  41. Nat Commun. 2019 Dec 5;10(1):5570 - PubMed
  42. Hum Mol Genet. 2011 Mar 1;20(5):867-79 - PubMed
  43. Neurology. 2010 Nov 30;75(22):2017-20 - PubMed
  44. J Mol Biol. 2020 Jan 3;432(1):206-230 - PubMed
  45. Autophagy. 2019 Jul;15(7):1182-1198 - PubMed
  46. Nat Rev Neurol. 2020 Feb;16(2):97-107 - PubMed
  47. Mol Neurodegener. 2017 Sep 29;12(1):70 - PubMed
  48. Neurobiol Dis. 2016 Jun;90:43-50 - PubMed
  49. J Cell Biol. 2008 Dec 1;183(5):795-803 - PubMed
  50. Nat Cell Biol. 2010 Feb;12(2):119-31 - PubMed
  51. Biochim Biophys Acta. 2010 Mar;1800(3):223-34 - PubMed
  52. Neurobiol Dis. 2014 Feb;62:381-6 - PubMed
  53. FEBS J. 2018 Apr;285(7):1185-1202 - PubMed
  54. Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6400-5 - PubMed
  55. Front Neurosci. 2020 May 25;14:498 - PubMed
  56. Sci Rep. 2012;2:1002 - PubMed
  57. Science. 2015 Dec 4;350(6265):aad2459 - PubMed
  58. Cell Stem Cell. 2016 Dec 1;19(6):709-724 - PubMed
  59. Biochem J. 2018 Jun 6;475(11):1861-1883 - PubMed
  60. Cell. 2016 Jul 14;166(2):314-327 - PubMed
  61. Dis Model Mech. 2017 Sep 1;10(9):1075-1087 - PubMed
  62. J Cell Biol. 2005 Nov 21;171(4):603-14 - PubMed
  63. Neurobiol Dis. 2013 Mar;51:35-42 - PubMed
  64. PLoS Biol. 2010 Jan 26;8(1):e1000298 - PubMed
  65. Mol Cell. 2014 Nov 6;56(3):360-75 - PubMed
  66. Biochem Soc Trans. 2018 Dec 17;46(6):1707-1712 - PubMed
  67. Cell Metab. 2013 Jun 4;17(6):941-953 - PubMed
  68. Hum Mol Genet. 2019 May 15;28(10):1645-1660 - PubMed
  69. J Parkinsons Dis. 2017;7(s1):S11-S19 - PubMed
  70. J Neurosci. 2012 Mar 21;32(12):4240-6 - PubMed
  71. Annu Rev Cell Dev Biol. 2020 Oct 6;36:237-264 - PubMed
  72. Nature. 2020 Dec;588(7837):344-349 - PubMed
  73. Mov Disord. 2020 Jul;35(7):1245-1248 - PubMed
  74. J Biol Chem. 2018 Mar 23;293(12):4566-4574 - PubMed
  75. Nat Genet. 2017 Oct;49(10):1511-1516 - PubMed
  76. Science. 1983 Feb 25;219(4587):979-80 - PubMed
  77. Nat Genet. 2014 Sep;46(9):989-93 - PubMed
  78. Genes Cells. 2016 Jul;21(7):772-88 - PubMed
  79. Biochem J. 2014 May 15;460(1):127-39 - PubMed
  80. J Cell Biol. 2018 May 7;217(5):1613-1622 - PubMed
  81. Autophagy. 2020 Feb;16(2):203-222 - PubMed
  82. Neurosci Res. 2020 Oct;159:34-39 - PubMed
  83. Hum Mol Genet. 2018 Sep 15;27(18):3189-3205 - PubMed
  84. Biochem Soc Trans. 2020 Oct 30;48(5):2185-2194 - PubMed
  85. J Cell Biol. 2016 Aug 1;214(3):275-91 - PubMed
  86. J Neurochem. 2016 Oct;139 Suppl 1:216-231 - PubMed
  87. Biochem J. 2016 Oct 15;473(20):3563-3580 - PubMed
  88. Science. 2018 Apr 6;360(6384):36-37 - PubMed
  89. Hum Mol Genet. 2019 Oct 1;28(19):3232-3243 - PubMed
  90. Mol Biol Cell. 2017 Mar 15;28(6):712-715 - PubMed
  91. Sci Adv. 2020 Nov 11;6(46): - PubMed
  92. Biochem J. 2018 Apr 9;475(7):1271-1293 - PubMed
  93. Cell Tissue Res. 2018 Jul;373(1):79-90 - PubMed
  94. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2389-2394 - PubMed
  95. EMBO Rep. 2013 May;14(5):450-7 - PubMed
  96. Front Cell Dev Biol. 2019 Jun 20;7:113 - PubMed
  97. Front Neurol. 2020 Aug 25;11:881 - PubMed
  98. Curr Neurol Neurosci Rep. 2018 Apr 3;18(5):21 - PubMed
  99. Essays Biochem. 2017 Dec 12;61(6):609-624 - PubMed
  100. Sci Rep. 2017 Aug 31;7(1):10300 - PubMed
  101. Nat Commun. 2019 Mar 1;10(1):994 - PubMed
  102. Nature. 2015 Aug 20;524(7565):309-314 - PubMed
  103. J Neural Transm (Vienna). 2013 Apr;120(4):509-16 - PubMed
  104. Elife. 2018 Nov 06;7: - PubMed
  105. Cells. 2019 Jul 12;8(7): - PubMed
  106. Neurobiol Dis. 2015 Jun;78:172-95 - PubMed
  107. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83 - PubMed
  108. EMBO Rep. 2012 Apr;13(4):378-85 - PubMed
  109. Nature. 2019 Jul;571(7766):565-569 - PubMed
  110. J Appl Physiol (1985). 2010 Jun;108(6):1745-56 - PubMed
  111. Mech Ageing Dev. 2020 Jan;185:111196 - PubMed
  112. Nat Commun. 2018 Feb 26;9(1):817 - PubMed
  113. J Biol Chem. 2014 May 16;289(20):13986-95 - PubMed
  114. EMBO Rep. 2015 Jun;16(6):709-18 - PubMed
  115. Autophagy. 2013 Nov 1;9(11):1758-69 - PubMed
  116. Sci Transl Med. 2016 Jun 8;8(342):342ra78 - PubMed

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