Abstract Details

Title LRRK2 G2019S Impairs Chaperone-Mediated Autophagy in Neurons

Topic Movement Disorders

Presentation(s) IN2 - (-)

Poster/Presentation
Number 001

Objective

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.

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
	No disclosure on file
	No disclosure on file
	No disclosure on file
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
Tahseen Mozaffar, MD, FAAN (University of California Irvine)	Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Dr. Mozaffar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Mozaffar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amicus. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Grifols. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas Gene Therapy. Dr. Mozaffar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer. Dr. Mozaffar has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Applied Therapeutics. The institution of Dr. Mozaffar has received research support from NIH. The institution of Dr. Mozaffar has received research support from Muscular Dystrophy Association. The institution of Dr. Mozaffar has received research support from Sanofi. The institution of Dr. Mozaffar has received research support from Argenx. The institution of Dr. Mozaffar has received research support from Amicus Therapeutics. The institution of Dr. Mozaffar has received research support from Astellas Gene Therpay. The institution of Dr. Mozaffar has received research support from Cartesian. The institution of Dr. Mozaffar has received research support from Cabaletta. Dr. Mozaffar has received personal compensation in the range of $500-$4,999 for serving as a Study Section Member with NIH.

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