PMID- 27541985
OWN - NLM
STAT- MEDLINE
DCOM- 20171113
LR  - 20181113
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 12
IP  - 11
DP  - 2016 Nov
TI  - Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration 
      in rats.
PG  - 2230-2247
AB  - Chaperone-mediated autophagy (CMA) involves the selective lysosomal degradation 
      of cytosolic proteins such as SNCA (synuclein alpha), a protein strongly implicated 
      in Parkinson disease (PD) pathogenesis. However, the physiological role of CMA 
      and the consequences of CMA failure in the living brain remain elusive. Here we 
      show that CMA inhibition in the adult rat substantia nigra via adeno-associated 
      virus-mediated delivery of short hairpin RNAs targeting the LAMP2A receptor, 
      involved in CMA's rate limiting step, was accompanied by intracellular 
      accumulation of SNCA-positive puncta, which were also positive for UBIQUITIN, and 
      in accumulation of autophagic vacuoles within LAMP2A-deficient nigral neurons. 
      Strikingly, LAMP2A downregulation resulted in progressive loss of nigral 
      dopaminergic neurons, severe reduction in striatal dopamine levels/terminals, 
      increased astro- and microgliosis and relevant motor deficits. Thus, this study 
      highlights for the first time the importance of the CMA pathway in the 
      dopaminergic system and suggests that CMA impairment may underlie PD 
      pathogenesis.
FAU - Xilouri, Maria
AU  - Xilouri M
AD  - a Center of Clinical Research, Experimental Surgery and Translational Research, 
      Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
FAU - Brekk, Oeystein Roed
AU  - Brekk OR
AD  - a Center of Clinical Research, Experimental Surgery and Translational Research, 
      Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
AD  - b University of Crete, School of Medicine , Heraklion , Crete , Greece.
FAU - Polissidis, Alexia
AU  - Polissidis A
AD  - a Center of Clinical Research, Experimental Surgery and Translational Research, 
      Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
FAU - Chrysanthou-Piterou, Margarita
AU  - Chrysanthou-Piterou M
AD  - c Research Unit of Histochemistry and Electron Microscopy , 1st Department of 
      Psychiatry, University of Athens Medical School, Eginition Hospital , Athens , 
      Greece.
FAU - Kloukina, Ismini
AU  - Kloukina I
AD  - d Center of Basic Research, Biomedical Research Foundation of the Academy of 
      Athens , Athens , Greece.
AD  - e Neurobiology Research Institute, Theodor Theohari Cozzika Foundation , Athens , 
      Greece.
FAU - Stefanis, Leonidas
AU  - Stefanis L
AD  - a Center of Clinical Research, Experimental Surgery and Translational Research, 
      Biomedical Research Foundation of the Academy of Athens , Athens , Greece.
AD  - f Second Department of Neurology , National and Kapodistrian University of Athens 
      Medical School , Athens , Greece.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160819
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - 0 (Molecular Chaperones)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sequestosome-1 Protein)
RN  - 0 (Sqstm1 protein, rat)
RN  - 0 (Ubiquitin)
RN  - 0 (alpha-Synuclein)
SB  - IM
MH  - Animals
MH  - *Autophagy
MH  - Behavior, Animal
MH  - Dependovirus/metabolism
MH  - Dopaminergic Neurons/*pathology/ultrastructure
MH  - Down-Regulation
MH  - Female
MH  - Gene Silencing
MH  - Genetic Vectors/metabolism
MH  - Lysosomal-Associated Membrane Protein 2/metabolism
MH  - Molecular Chaperones/*metabolism
MH  - Neostriatum/metabolism/pathology
MH  - Nerve Degeneration/*pathology
MH  - Phenotype
MH  - RNA, Small Interfering/metabolism
MH  - Rats, Wistar
MH  - Sequestosome-1 Protein/metabolism
MH  - Substantia Nigra/metabolism/pathology
MH  - Transduction, Genetic
MH  - Ubiquitin/metabolism
MH  - Vacuoles/metabolism/ultrastructure
MH  - alpha-Synuclein/metabolism
PMC - PMC5103347
OTO - NOTNLM
OT  - LAMP2A
OT  - Parkinson disease
OT  - chaperone-mediated autophagy
OT  - lysosomes
OT  - synuclein alpha
EDAT- 2016/11/02 06:00
MHDA- 2017/11/14 06:00
PMCR- 2017/08/19
CRDT- 2016/08/20 06:00
PHST- 2016/11/02 06:00 [pubmed]
PHST- 2017/11/14 06:00 [medline]
PHST- 2016/08/20 06:00 [entrez]
PHST- 2017/08/19 00:00 [pmc-release]
AID - 1214777 [pii]
AID - 10.1080/15548627.2016.1214777 [doi]
PST - ppublish
SO  - Autophagy. 2016 Nov;12(11):2230-2247. doi: 10.1080/15548627.2016.1214777. Epub 
      2016 Aug 19.