PMID- 30791416
OWN - NLM
STAT- MEDLINE
DCOM- 20190604
LR  - 20200225
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 20
IP  - 4
DP  - 2019 Feb 19
TI  - Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded 
      Protein Toxicity.
LID - 10.3390/ijms20040901 [doi]
LID - 901
AB  - The aim of this review is to critically analyze promises and limitations of 
      pharmacological inducers of autophagy against protein misfolding-associated 
      neurodegeneration. Effective therapies against neurodegenerative disorders can be 
      developed by regulating the "self-defense" equipment of neurons, such as 
      autophagy. Through the degradation and recycling of the intracellular content, 
      autophagy promotes neuron survival in conditions of trophic factor deprivation, 
      oxidative stress, mitochondrial and lysosomal damage, or accumulation of 
      misfolded proteins. Autophagy involves the activation of self-digestive pathways, 
      which is different for dynamics (macro, micro and chaperone-mediated autophagy), 
      or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative 
      disorders share common pathogenic mechanisms, including the impairment of 
      autophagic flux, which causes the inability to remove the neurotoxic oligomers of 
      misfolded proteins. Pharmacological activation of autophagy is typically achieved 
      by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic 
      complex 1 (mTORC1), removing its autophagy suppressor activity observed under 
      physiological conditions; acting in this way, rapamycin provided the first proof 
      of principle that pharmacological autophagy enhancement can induce 
      neuroprotection through the facilitation of oligomers' clearance. The demand for 
      effective disease-modifying strategies against neurodegenerative disorders is 
      currently stimulating the development of a wide number of novel molecules, as 
      well as the re-evaluation of old drugs for their pro-autophagic potential.
FAU - Thellung, Stefano
AU  - Thellung S
AD  - Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza 
      per la Ricerca Biomedica (CEBR), Universita di Genova, 16132 Genova, Italy. 
      stefano.thellung@unige.it.
FAU - Corsaro, Alessandro
AU  - Corsaro A
AD  - Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza 
      per la Ricerca Biomedica (CEBR), Universita di Genova, 16132 Genova, Italy. 
      ale.corsaro@unige.it.
FAU - Nizzari, Mario
AU  - Nizzari M
AD  - Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza 
      per la Ricerca Biomedica (CEBR), Universita di Genova, 16132 Genova, Italy. 
      mario.nizzari@unige.it.
FAU - Barbieri, Federica
AU  - Barbieri F
AD  - Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza 
      per la Ricerca Biomedica (CEBR), Universita di Genova, 16132 Genova, Italy. 
      federica.barbieri@unige.it.
FAU - Florio, Tullio
AU  - Florio T
AUID- ORCID: 0000-0002-2394-996X
AD  - Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza 
      per la Ricerca Biomedica (CEBR), Universita di Genova, 16132 Genova, Italy. 
      tullio.florio@unige.it.
AD  - IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy. 
      tullio.florio@unige.it.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20190219
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Biomarkers)
RN  - 0 (Protein Aggregates)
SB  - IM
MH  - Animals
MH  - Autophagy/*drug effects/genetics
MH  - Biomarkers
MH  - *Drug Discovery/methods
MH  - Humans
MH  - Lysosomes/drug effects/genetics/metabolism
MH  - Mitochondria/drug effects/genetics/metabolism
MH  - Neurodegenerative Diseases/drug therapy/etiology/metabolism/pathology
MH  - Neuroprotection/*drug effects
MH  - Protein Aggregates
MH  - Protein Aggregation, Pathological
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Folding
MH  - Protein Multimerization
MH  - Proteostasis Deficiencies/drug therapy/etiology/metabolism/pathology
MH  - Structure-Activity Relationship
PMC - PMC6412775
OTO - NOTNLM
OT  - autophagy
OT  - mTOR
OT  - neurodegenerative diseases
OT  - protein misfolding
OT  - rapamycin
COIS- The authors have no conflict of interest to declare.
EDAT- 2019/02/23 06:00
MHDA- 2019/06/05 06:00
PMCR- 2019/02/01
CRDT- 2019/02/23 06:00
PHST- 2019/01/24 00:00 [received]
PHST- 2019/02/11 00:00 [revised]
PHST- 2019/02/14 00:00 [accepted]
PHST- 2019/02/23 06:00 [entrez]
PHST- 2019/02/23 06:00 [pubmed]
PHST- 2019/06/05 06:00 [medline]
PHST- 2019/02/01 00:00 [pmc-release]
AID - ijms20040901 [pii]
AID - ijms-20-00901 [pii]
AID - 10.3390/ijms20040901 [doi]
PST - epublish
SO  - Int J Mol Sci. 2019 Feb 19;20(4):901. doi: 10.3390/ijms20040901.