Abstract Details

Title LRRK2 G2019S Impairs Chaperone-Mediated Autophagy in Neurons

Topic Movement Disorders

Presentation(s) S13 - (-)

Poster/Presentation
Number 003

Background LRRK2 G2019S mutation is the major genetic cause of PD, and most LRRK2 G2019S PD cases exhibit ?-synuclein containing Lewy body pathology. Since LRRK2 has the consensus sequences required for CMA degradation, we investigated the relationship between LRRK2 G2019S and CMA, the pathway for ?-synuclein lysosomal degradation, in neurons.

Objective

Design/Methods We used a novel CMA reporter in dopaminergic neuronal cultures derived from LRRK2 G2019S and wild type (wt) mice to study CMA activity. We also investigated whether LRRK2 G2019S affected ?-synuclein association with a lysosomal marker, lysosomal membrane associated protein type 2 (LAMP2) in neuronal cultures. Finally, we studied the levels of the key CMA component, lysosomal membrane associated protein type 2A (LAMP-2A), in post-mortem brain from two LRRK2 G2019S PD cases and two age-matched controls.

Results We found that decreased CMA activity in neurons from LRRK2 G2019S mice than wt mice as reflected by the number of lysosomes associated with CMA reporter per cell (2.73 ± 0.66 in LRRK2 G2019S vs.11.73 ±1.43 in wt, p<0.01). In addition, LRRK2 G2019S enhances ?-synuclein colocalization with LAMP2 in neuronal cultures (colocalization coefficient, 0.61± 0.05 in LRRK2 G2019S vs. 0.41± 0.33 in wt, p<0.05), apparently due to the accumulation of ?-synuclein on the LRRK2 G2019S lysosomal membrane as a result of the CMA blockade. In LRRK2 G2019S PD brain, we found increased LAMP-2A levels (2.42 ± 0.27 in LRRK2 G2019S PD cases vs. 1.00 ± 0.18 in controls), which could be due to compensatory responses seen in CMA dysfunction.

Conclusions LRRK2 G2019S can interfere with CMA in neurons, which appears to cause ?-synuclein accumulation. This might underlie the ?-synuclein pathology in LRRK2 G2019S PD cases.

Authors/Disclosures
Sheng-Han Kuo, MD, FAAN (Columbia University) PRESENTER	Dr. Kuo has nothing to disclose.
	No disclosure on file
Vincenzo Cimino	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Dileep R. Yavagal, MD, FAAN (University of Miami Miller School of Medicine)	Dr. Yavagal has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vascular Dynamics. Dr. Yavagal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Guidepoint. The institution of Dr. Yavagal has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Yavagal has received personal compensation in the range of $0-$499 for serving as a Consultant for Medtronic. Dr. Yavagal has received personal compensation in the range of $0-$499 for serving as a Consultant for Cerenovus/Johnson & Johnson. Dr. Yavagal has received personal compensation in the range of $0-$499 for serving as a Consultant for Stryker. Dr. Yavagal has received personal compensation in the range of $0-$499 for serving as a Consultant for Poseydon. Dr. Yavagal has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Athersys. Dr. Yavagal has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gravity Medical Technology. Dr. Yavagal has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Poseydon. Dr. Yavagal has stock in Poseydon. Dr. Yavagal has stock in Galaxy Therapeutics. Dr. Yavagal has stock in Stentrode. Dr. Yavagal has stock in Gravity Medical. Dr. Yavagal has stock in Gravity Medical Technology. Dr. Yavagal has stock in Athersys. Dr. Yavagal has stock in Rapid Medical . Dr. Yavagal has received intellectual property interests from a discovery or technology relating to health care. Dr. Yavagal has received personal compensation in the range of $5,000-$9,999 for serving as a Medicolegal Expert with Royal Carribean Cruise Line. Dr. Yavagal has received personal compensation in the range of $5,000-$9,999 for serving as a Medicolegal Consultant with Carnival Cruise Line.
Roy Alcalay, MD (Columbia University)	Dr. Alcalay has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genzyme/Sanofi. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gain Therapeutics. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vanqua Bio. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Capsida. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Servier. The institution of Dr. Alcalay has received research support from Michael J. Fox Foundation. The institution of Dr. Alcalay has received research support from Parkinson's Foundation. The institution of Dr. Alcalay has received research support from Silverstein Foundation. Dr. Alcalay has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant with Parkinson's Foundation.
	No disclosure on file
David Sulzer, PhD (Columbia University Medical School)	No disclosure on file

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