A Clue in Parkinson Disease

An AAN Poster Brief

Bret S. Stetka, MD; Sheng-Han Kuo, MD

Disclosures

April 09, 2013

Editor's Note:
This year's American Academy of Neurology Annual Meeting featured an Integrative Neuroscience Session looking at new insights into the molecular mechanisms associated with Parkinson disease (PD). At the session's Poster Rounds, Medscape spoke with Sheng-Han Kuo, MD, Assistant Professor of Neurology at Columbia University Medical Center, New York, New York, about work that he and his colleagues are doing to investigate potential genetic and molecular causes of PD.

Medscape: Dr. Kuo, what exactly is chaperone-mediated autophagy (CMA)?

Dr. Kuo: CMA is to a process in which a "chaperone" molecule binds to cytosolic proteins and traffics them to lysosomes for degradation. Hence, it's the cell's way of selectively degrading proteins. CMA is a normal physiologic process for protein quality control, especially in the presence of oxidative stress. It selectively degrades proteins with CMA motifs.

Medscape: Your study looked at impaired CMA in a genetic variant of PD. What can you tell us about your research?

Dr. Kuo: We are looking specifically at CMA in neurons, which is impaired in LRRK2 G2019S mutants. LRRK2 mutations are associated with PD, and we looked at whether or not LRRK2's protein product goes through CMA. In order to go through the CMA pathway, a protein must contain consensus motifs, and our work shows that LRRK2's encoded protein actually has 8, since it's a large molecule; in both in vitro and in vivo studies, we have strong evidence that normal LRRK2 can be degraded by CMA.

But of note, we found that the LRRK2 G2019S mutation blocks CMA in neurons by using a novel CMA reporter. We also further confirmed the effects of LRRK2 G2019S mutations on CMA in mouse models, postmortem PD brains, , and dopaminergic neurons derived from stem cells of patients with LRRK2 G2019S mutations and PD.

We further found out that if we put purified LRRK2 G2019S protein and alpha-synuclein protein in the presence of lysosomes, not only does the LRRK2 G2019S protein block alpha-synuclein degradation by CMA, but it also causes alpha-synuclein to form oligomers on the lysosomal membrane, providing a toxic coincidence of these 2 proteins. This could also be a mechanism of how LRRK2 G2019S causes alpha-synuclein pathology in PD.

Medscape: So, impaired CMA leads to abnormal synuclein accumulation in the brain, which leads to Lewy body formation, a pathologic hallmark of PD?

Dr. Kuo: Yes. This is our hypothesis. Although synuclein can probably be degraded through other pathways, for example proteosome pathways or macroautophagy pathways, with age the impaired CMA may still lead to a gradual build-up of synuclein.

Medscape: What are the potential therapeutic implications of your work?

Dr. Kuo: We have characterized that CMA could explain both alpha-synuclein point mutations and LRRK2 mutations leading to alpha-synuclein accumulation pathology in PD. Therefore, enhancing CMA could be a therapeutic target for PD disease-modifying treatment.

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