Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson's Disease.

Publisher: MDPI AG Country of Publication: Switzerland NLM ID: 101606588 Publication Model: Electronic Cited Medium: Print ISSN: 2077-0383 (Print) Linking ISSN: 20770383 NLM ISO Abbreviation: J Clin Med Subsets: PubMed not MEDLINE

Original Publication: Basel, Switzerland : MDPI AG, [2012]-

The association between Parkinson's disease (PD) and mutations in genes involved in lysosomal and mitochondrial function has been previously reported. However, little is known about the involvement of other genes or cellular mechanisms. We aim to identify novel genetic associations to better understand the pathogenesis of PD. We performed WES in a cohort of 32 PD patients and 30 age-matched controls. We searched for rare variants in 1667 genes: PD-associated, related to lysosomal function and mitochondrial function and TFEB-regulated. When comparing the PD patient cohort with that of age matched controls, a statistically significant burden of rare variants in the previous group of genes were identified. In addition, the Z-score calculation, using the European population database (GnomAD), showed an over-representation of particular variants in 36 genes. Interestingly, 11 of these genes are implicated in mitochondrial function and 18 are TFEB-regulated genes. Our results suggest, for the first time, an involvement of TFEB-regulated genes in the genetic susceptibility to PD. This is remarkable as TFEB factor has been reported to be sequestered inside Lewy bodies, pointing to a role of TFEB in the pathogenesis of PD. Our data also reinforce the involvement of lysosomal and mitochondrial mechanisms in PD.

J Parkinsons Dis. 2021;11(1):45-60. (PMID: 33074190)
Ann Neurol. 2006 May;59(5):859-62. (PMID: 16634032)
Mol Neurodegener. 2017 Jan 25;12(1):11. (PMID: 28122627)
Nature. 2021 Nov;599(7886):650-656. (PMID: 34732887)
Ann Neurol. 2002 Aug;52(2):211-9. (PMID: 12210792)
Lancet. 2004 Sep 4-10;364(9437):875-82. (PMID: 15351195)
Exp Gerontol. 2020 Sep;138:110997. (PMID: 32554091)
Cells. 2021 Mar 16;10(3):. (PMID: 33809527)
Orv Hetil. 2020 May 01;161(20):821-828. (PMID: 32364361)
Arch Neurol. 2004 Nov;61(11):1777-9. (PMID: 15534189)
Science. 2009 Jul 24;325(5939):473-7. (PMID: 19556463)
Neuropsychopharmacology. 2019 Apr;44(5):837-849. (PMID: 29855563)
PLoS One. 2016 Sep 15;11(9):e0163029. (PMID: 27631370)
Neurol Sci. 2002 Sep;23 Suppl 2:S59-60. (PMID: 12548343)
Hum Mol Genet. 2011 Oct 1;20(19):3852-66. (PMID: 21752829)
Cells. 2019 Apr 19;8(4):. (PMID: 31010158)
Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1539-1555. (PMID: 28215579)
Lancet. 2015 Aug 29;386(9996):896-912. (PMID: 25904081)
Mov Disord. 2015 Oct;30(12):1591-601. (PMID: 26474316)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
Neurosci Lett. 2010 Dec 17;486(3):235-9. (PMID: 20887775)
Front Genet. 2019 Oct 31;10:1061. (PMID: 31737044)
IUBMB Life. 2001 Sep-Nov;52(3-5):135-41. (PMID: 11798025)
Arch Neurol. 2007 Apr;64(4):553-7. (PMID: 17420318)
Clin Genet. 2018 Mar;93(3):712-718. (PMID: 29120065)
Nucleic Acids Res. 2016 Jan 4;44(D1):D1251-7. (PMID: 26450961)
J Neurosci. 2016 Feb 24;36(8):2425-37. (PMID: 26911690)
Cell Tissue Res. 2018 Jul;373(1):9-20. (PMID: 29536161)
Int J Neurosci. 2020 Apr;130(4):319-321. (PMID: 31613174)
Autophagy. 2015;11(9):1443-57. (PMID: 26207393)
Mov Disord. 2016 Jun;31(6):791-801. (PMID: 26923732)
Brain. 2017 Dec 1;140(12):3191-3203. (PMID: 29140481)
Mov Disord. 2020 Jul;35(7):1245-1248. (PMID: 32267580)
J Neurochem. 2016 Oct;139 Suppl 1:59-74. (PMID: 27090875)
Mov Disord. 2018 Oct;33(10):1591-1600. (PMID: 30256453)
BMB Rep. 2020 Jan;53(1):56-63. (PMID: 31818366)
Neuromuscul Disord. 2015 Apr;25(4):333-9. (PMID: 25660390)
J Pers Med. 2019 Aug 17;9(3):. (PMID: 31426520)
Bioinformatics. 2019 Jun 1;35(11):1978-1980. (PMID: 30376034)
Nat Commun. 2016 Jun 09;7:11803. (PMID: 27278822)
Mov Disord. 2019 May;34(5):614-624. (PMID: 30726573)
Neurobiol Aging. 2011 Nov;32(11):2108.e1-5. (PMID: 21782285)
Autophagy. 2013 Aug;9(8):1244-6. (PMID: 23715007)

Keywords: Parkinson’s disease; TFEB; WES; lysosomal; lysosomal diseases; mitochondrial; mitochondrial function; risk-factor

Date Created: 20220325 Latest Revision: 20220329

20221213

PMC8951534

10.3390/jcm11061749

35330074