Chaperone-mediated autophagy markers in Parkinson disease brains.
OBJECTIVE
To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD).


METHODS
Postmortem observational study.


METHODS
University Department of Clinical Neuroscience, Institute of Neurology, University College London.


METHODS
Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains.


METHODS
Lysosomal-associated membrane protein 2A (LAMP2A) and heat shock cognate 70 (hsc70) protein levels were compared in the substantia nigra pars compacta and amygdala of PD, AD, and control brain samples. To provide insight into the turnover of α-synuclein, degradation pathways for this protein were studied in a dopaminergic cell line.


RESULTS
The expression levels of the chaperone-mediated autophagy proteins LAMP2A and hsc70 were significantly reduced in the substantia nigra pars compacta and amygdala of PD brains compared with age-matched AD and control brain samples. Lewy bodies in these regions contained autophagy-related proteins. We demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of α-synuclein.


CONCLUSIONS
These findings suggest that there is reduced chaperone-mediated autophagy activity in the PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation, and suggest that this pathway may be a suitable therapeutic target in PD.
Alvarez-Erviti
Lydia
L
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, University of Navarra, Pamplona, Spain.
Rodriguez-Oroz
Maria C
MC
Cooper
J Mark
JM
Caballero
Cristina
C
Ferrer
Isidro
I
Obeso
Jose A
JA
Schapira
Anthony H V
AH
D000544:Alzheimer Disease / Q000473:pathology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D011180:Postmortem Changes; D034741:RNA, Small Interfering / Q000494:pharmacology; D018709:Statistics, Nonparametric; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D050883:HSC70 Heat-Shock Proteins; D006388:Hemagglutinins; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D034741:RNA, Small Interfering; D051844:alpha-Synuclein