OBJECTIVE: To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD). DESIGN: Postmortem observational study. SETTING: University Department of Clinical Neuroscience, Institute of Neurology, University College London. SUBJECTS: Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains. MAIN OUTCOME MEASURE: 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.
OBJECTIVE: To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD). DESIGN: Postmortem observational study. SETTING: University Department of Clinical Neuroscience, Institute of Neurology, University College London. SUBJECTS: Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains. MAIN OUTCOME MEASURE: 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.
Authors: David A Loeffler; Lynnae M Smith; Mary P Coffey; Jan O Aasly; Peter A LeWitt Journal: J Neural Transm (Vienna) Date: 2015-11-03 Impact factor: 3.575
Authors: Amirthaa Suntharalingam; Jose F Abisambra; John C O'Leary; John Koren; Bo Zhang; Myung Kuk Joe; Laura J Blair; Shannon E Hill; Umesh K Jinwal; Matthew Cockman; Adam S Duerfeldt; Stanislav Tomarev; Brian S J Blagg; Raquel L Lieberman; Chad A Dickey Journal: J Biol Chem Date: 2012-10-03 Impact factor: 5.157