PMID- 26601773 OWN - NLM STAT- MEDLINE DCOM- 20160930 LR - 20211203 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 313 DP - 2016 Jan 28 TI - Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease. PG - 162-73 LID - S0306-4522(15)01019-2 [pii] LID - 10.1016/j.neuroscience.2015.11.030 [doi] AB - A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Duarte-Silva, S AU - Duarte-Silva S AD - Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal. FAU - Silva-Fernandes, A AU - Silva-Fernandes A AD - Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal. FAU - Neves-Carvalho, A AU - Neves-Carvalho A AD - Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal. FAU - Soares-Cunha, C AU - Soares-Cunha C AD - Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal. FAU - Teixeira-Castro, A AU - Teixeira-Castro A AD - Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal. FAU - Maciel, P AU - Maciel P AD - Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimaraes, Portugal. Electronic address: pmaciel@ecsaude.uminho.pt. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151119 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Central Nervous System Agents) RN - 0 (Lithium Compounds) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.19.12 (Ataxin-3) RN - EC 3.4.19.12 (Atxn3 protein, mouse) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Ataxin-3/metabolism MH - Autophagy/*drug effects/physiology MH - Brain/drug effects/metabolism/pathology MH - Caenorhabditis elegans MH - Central Nervous System Agents/administration & dosage/*toxicity MH - Disease Models, Animal MH - Drug Evaluation, Preclinical MH - Drug Therapy, Combination MH - Lithium Compounds/administration & dosage/*toxicity MH - Locomotion/drug effects/physiology MH - Machado-Joseph Disease/*drug therapy/pathology/physiopathology MH - Male MH - Mice, Inbred C57BL MH - Motor Activity/drug effects/physiology MH - Neurotoxicity Syndromes/pathology/*physiopathology MH - Sirolimus/administration & dosage/*analogs & derivatives/toxicity MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism OTO - NOTNLM OT - animal models OT - ataxia OT - autophagy OT - behavior OT - polyglutamine diseases OT - therapy EDAT- 2015/11/26 06:00 MHDA- 2016/10/01 06:00 CRDT- 2015/11/26 06:00 PHST- 2015/09/22 00:00 [received] PHST- 2015/11/09 00:00 [revised] PHST- 2015/11/13 00:00 [accepted] PHST- 2015/11/26 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2016/10/01 06:00 [medline] AID - S0306-4522(15)01019-2 [pii] AID - 10.1016/j.neuroscience.2015.11.030 [doi] PST - ppublish SO - Neuroscience. 2016 Jan 28;313:162-73. doi: 10.1016/j.neuroscience.2015.11.030. Epub 2015 Nov 19.