title: Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease.
abstract: The accumulation of misfolded proteins in neurons, leading to the formation of cytoplasmic and nuclear aggregates, is a common theme in age-related neurodegenerative diseases, possibly due to disturbances of the proteostasis and insufficient activity of cellular protein clearance pathways. Lithium is a well-known autophagy inducer that exerts neuroprotective effects in different conditions and has been proposed as a promising therapeutic agent for several neurodegenerative diseases. We tested the efficacy of chronic lithium (10.4 mg/kg) treatment in a transgenic mouse model of Machado-Joseph disease, an inherited neurodegenerative disease, caused by an expansion of a polyglutamine tract within the protein ataxin-3. A battery of behavioral tests was used to assess disease progression. In spite of activating autophagy, as suggested by the increased levels of Beclin-1, Atg7, and LC3-II, and a reduction in the p62 protein levels, lithium administration showed no overall beneficial effects in this model concerning motor performance, showing a positive impact only in the reduction of tremors at 24 weeks of age. Our results do not support lithium chronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Duarte-Silva
authors.forename: Andreia
authors.initials: A
authors.lastname: Neves-Carvalho
authors.forename: Carina
authors.initials: C
authors.lastname: Soares-Cunha
authors.forename: Andreia
authors.initials: A
authors.lastname: Teixeira-Castro
authors.forename: Pedro
authors.initials: P
authors.lastname: Oliveira
authors.forename: Anabela
authors.initials: A
authors.lastname: Silva-Fernandes
authors.forename: Patrícia
authors.initials: P
authors.lastname: Maciel
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000067699:Ataxin-3; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D017827:Machado-Joseph Disease / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009465:Neuromuscular Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014202:Tremor / Q000188:drug therapy / Q000503:physiopathology; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C502661:Atg7 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009465:Neuromuscular Agents; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D000071193:Autophagy-Related Protein 7; D018021:Lithium Chloride
references.citation: J Neurosci. 2008 Mar 19;28(12):3051-9
references.pmid: 18354008
references.citation: Mov Disord. 2007 Mar 15;22(4):570-3
references.pmid: 17260335
references.citation: Biochem Biophys Res Commun. 2001 Jan 26;280(3):720-5
references.pmid: 11162580
references.citation: Cell. 1996 Nov 1;87(3):493-506
references.pmid: 8898202
references.citation: J Clin Psychiatry. 1995 Jul;56(7):283-7
references.pmid: 7615481
references.citation: Exp Neurol. 2004 Jan;185(1):47-62
references.pmid: 14697318
references.citation: Lab Anim. 2002 Jan;36(1):20-42
references.pmid: 11831737
references.citation: Therapie. 1996 Mar-Apr;51(2):101-6
references.pmid: 8763043
references.citation: Mamm Genome. 1997 Oct;8(10):711-3
references.pmid: 9321461
references.citation: Science. 2004 Aug 27;305(5688):1292-5
references.pmid: 15333840
references.citation: Cerebellum. 2012 Sep;11(3):771-4
references.pmid: 22090366
references.citation: Trends Neurosci. 2000 May;23(5):222-9
references.pmid: 10782128
references.citation: Brain Res. 2003 Jul 4;977(1):38-45
references.pmid: 12788511
references.citation: Autophagy. 2006 Apr-Jun;2(2):132-4
references.pmid: 16874097
references.citation: Prog Neurobiol. 2011 Sep 15;95(1):26-48
references.pmid: 21740957
references.citation: Encephale. 1990 Jul-Aug;16(4):251-9
references.pmid: 2145146
references.citation: Mamm Genome. 2000 Sep;11(9):725-8
references.pmid: 10967129
references.citation: Neuroscience. 2008 Aug 26;155(3):567-72
references.pmid: 18640245
references.citation: Hum Mol Genet. 2002 May 1;11(9):1075-94
references.pmid: 11978767
references.citation: Med J Aust. 1981 Apr 18;1(8):407-9
references.pmid: 6454826
references.citation: J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22
references.pmid: 15751225
references.citation: Neuron. 2007 Jun 21;54(6):854-6
references.pmid: 17582326
references.citation: Pharmacogenomics J. 2005;5(2):102-11
references.pmid: 15668729
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: Brain Res Bull. 2003 Aug 30;61(4):375-83
references.pmid: 12909280
references.citation: Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2010 Feb;27(1):23-8
references.pmid: 20140862
references.citation: Brain Res. 2004 Oct 22;1024(1-2):183-92
references.pmid: 15451381
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455-9
references.pmid: 8710892
references.citation: Curr Biol. 1996 Dec 1;6(12):1664-8
references.pmid: 8994831
references.citation: Nat Rev Neurosci. 2009 Jul;10(7):519-29
references.pmid: 19513088
references.citation: J Cell Biol. 2005 Sep 26;170(7):1101-11
references.pmid: 16186256
references.citation: Cell. 1989 Nov 3;59(3):411-9
references.pmid: 2553271
references.citation: J Neurochem. 1997 Dec;69(6):2336-44
references.pmid: 9375664
references.citation: Int J Biochem Cell Biol. 2004 Dec;36(12):2445-62
references.pmid: 15325584
references.citation: Neuroscience. 2011 Dec 29;199:292-302
references.pmid: 22056603
references.citation: Brain. 2011 May;134(Pt 5):1400-15
references.pmid: 21478185
references.citation: J Cell Biol. 2005 Oct 10;171(1):87-98
references.pmid: 16203860
references.citation: BMC Neurol. 2011 Oct 24;11:131
references.pmid: 22023810
references.citation: Pharmacopsychiatry. 1995 Mar;28(2):35-44
references.pmid: 7624385
references.citation: Brain Res Rev. 2011 Jun 24;67(1-2):252-9
references.pmid: 21356243
references.citation: Nature. 2008 Feb 28;451(7182):1069-75
references.pmid: 18305538
references.citation: Neuropharmacology. 2002 Dec;43(7):1173-9
references.pmid: 12504924
references.citation: Autophagy. 2008 Feb;4(2):151-75
references.pmid: 18188003
references.citation: J Clin Psychiatry. 2003;64 Suppl 5:18-24
references.pmid: 12720480
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:789-813
references.pmid: 11264477
references.citation: Hum Mol Genet. 2006 Feb 1;15(3):433-42
references.pmid: 16368705
references.citation: Neuron. 1997 Aug;19(2):333-44
references.pmid: 9292723
references.citation: Methods Enzymol. 2008;451:493-520
references.pmid: 19185737
references.citation: Cerebellum. 2013 Dec;12(6):892-901
references.pmid: 23812869
references.citation: J Neurochem. 2011 Aug;118(3):317-25
references.pmid: 21599666
references.citation: Eur J Pharmacol. 2000 Mar 31;392(3):117-23
references.pmid: 10762662
references.citation: Neurogenetics. 1997 Sep;1(2):103-12
references.pmid: 10732811
references.citation: Psychopharmacology (Berl). 2001 Oct;158(1):100-6
references.pmid: 11685390
references.citation: Neurobiol Aging. 2007 Nov;28(11):1689-99
references.pmid: 16963164
references.citation: Nat Genet. 2004 Jun;36(6):585-95
references.pmid: 15146184
references.citation: J Neurosci. 1999 Apr 15;19(8):3248-57
references.pmid: 10191337
references.citation: Neurochem Int. 1993 Apr;22(4):395-403
references.pmid: 8384505
references.citation: Mov Disord. 2014 Apr;29(4):568-73
references.pmid: 24399647
references.citation: Mol Interv. 2004 Oct;4(5):259-72
references.pmid: 15471909
references.citation: Int J Neuropsychopharmacol. 2000 Jun;3(2):175-186
references.pmid: 11343594
references.citation: Arch Psychiatr Nervenkr (1970). 1981;231(1):41-60
references.pmid: 6797383
references.citation: Neurobiol Dis. 2010 Oct;40(1):163-76
references.pmid: 20510362
references.citation: Cell Death Differ. 2009 Jan;16(1):46-56
references.pmid: 18636076
references.citation: Autophagy. 2006 Jul-Sep;2(3):224-5
references.pmid: 16874096
references.citation: Hum Mol Genet. 2002 May 1;11(9):1107-17
references.pmid: 11978769
references.citation: J Genet Hum. 1981 Sep;29(3):203-9
references.pmid: 6950024
references.citation: Cerebellum. 2008;7(2):125-37
references.pmid: 18418689
references.citation: Brain. 2010 Jan;133(Pt 1):93-104
references.pmid: 20007218
references.citation: Mol Biol Cell. 2008 Dec;19(12):5360-72
references.pmid: 18843052
references.citation: J Neurosci. 2004 Nov 10;24(45):10266-79
references.pmid: 15537899
references.citation: Postgrad Med J. 2004 Jun;80(944):363-5
references.pmid: 15192175
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7
references.pmid: 18250315
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):6210-5
references.pmid: 12732732
references.citation: J Biol Chem. 1999 Mar 5;274(10):6039-42
references.pmid: 10037682
references.citation: Acta Pharmacol Sin. 2011 Sep;32(9):1089-99
references.pmid: 21804578
references.citation: PLoS Med. 2007 May;4(5):e182
references.pmid: 17535104
references.citation: Nat Rev Drug Discov. 2007 Apr;6(4):304-12
references.pmid: 17396135
references.citation: Neurology. 1998 Oct;51(4):1225-6
references.pmid: 9781572
references.citation: Int J Psychiatry Med. 2002;32(1):103-8
references.pmid: 12075913
references.citation: Neurotherapeutics. 2014 Apr;11(2):433-49
references.pmid: 24477711
references.citation: J Biol Chem. 2003 Jul 4;278(27):25009-13
references.pmid: 12719433
references.citation: Neurobiol Dis. 2008 Jul;31(1):89-101
references.pmid: 18502140
references.citation: Behav Brain Res. 2005 Feb 10;157(1):91-8
references.pmid: 15617775
references.citation: J Biol Chem. 2000 Mar 17;275(11):7583-90
references.pmid: 10713065
references.citation: CNS Drugs. 2006;20(1):29-42
references.pmid: 16396522
references.citation: Neurosci Res. 2011 Aug;70(4):339-48
references.pmid: 21624403
references.citation: Trends Cell Biol. 2004 Feb;14(2):70-7
references.pmid: 15102438
references.citation: Prog Neurobiol. 2012 May;97(2):239-57
references.pmid: 22133674