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Functional Analysis of LRRK2: Focus on Autophagy

This grant builds upon the research from a prior grant: Functional Analysis of LRRK2

Promising Outcomes of Original Grant:
The overall purpose of the original grant was to utilize pre-clinical and human model systems to better understand LRRK biology. The original aims proposed were to 1) use pre-clinical model genetics to identify genetic interactors with LRRK2 2) Characterize LRRK2 KO model with respect to the dopaminergic system and 3) create human lines containing PD associated LRRK2 mutations to understand LRRK2 signalling in a human context.

Currently, we have identified a number of promising genetic loci interacting with LRRK2  in the pre-clinical model we are characterizing. We have also demonstrated a dramatic phenotype in LRRK2 KO kidney including synuclein aggregation and impairment of the lysosomal-autophagic pathway. Finally, we have shown that LRRK2 is very abundant in immunologically related tissues and that LPS can upregulate LRKR2 mRNA through the toll like receptor.

Objectives for Supplemental Investigation: 
Some of the findings which we generated from our original proposal as well as new and emerging concepts in the field have suggested that 1) autophagy may play a critical role in PD and 2) LRRK2 my play a key role in autophagy. Accordingly, the supplemental aims of our proposal examine more carefully the role of autophagy in basic LRRK2 biology, in the immune system, and in mitochondrial quality control.

Importance of This Research for the Development of a New PD Therapy:
If we can understand what LRRK2 does normally or under pathological conditions, we can then try and manipulate these mechanisms to halt the underlying disease process associated with PD.



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