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Research Summary

The overall goal of the LaVoie lab is to elucidate the early molecular events that are responsible for the diverse pathology associated with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson’s disease (PD).  We approach this devastating progressive movement disorder from both the perspective that specific inherited gene mutations linked to familial forms of these diseases can provide valuable insight, as well as maintaining a focus on aspects of the far more common sporadic forms. The LaVoie lab employs a diverse array of state-of-the-art tools to accomplish these goals including a series of novel knockin animal models, iPSC-based neuronal and glial cultures, and CRISPR/Cas9 genome editing.

Our focus on familial PD is centered on pathogenic mutations in the Parkin and LRRK2 genes.  Parkin is an ubiquitin E3 ligase which is highly expressed in neurons.  Autosomal recessive, loss-of-function mutations in the Parkin gene are associated with an often early onset form of Parkinson’s disease.  The precise role of parkin within the neuron is not clear, however, data from multiple model organisms strongly support both homeostatic and pro-survival functions of parkin that impact mitochondrial biology.  Our ongoing work seeks to understand how a primarily cytosolic protein such as parkin possesses such a potent influence on mitochondria.

LRRK2 is a large multi-domain kinase linked to PD via autosomal dominant inheritance of several mutations that span the entire protein.  Given the complex nature of the LRRK2 protein itself, and the fact that PD-linked mutations occur in multiple domains, a primary goal of our work is to understand the physiological function and regulation of wild-type LRRK2.  Then, we hope to uncover divergent behaviors and consequences of various PD-linked mutants (e.g. R1441C/G/H, Y1699C, G2019S, I2020T).  Our recent work has shown that the highly active LRRK2 dimer resides at the cell membrane, regulates lysosomal function and influences the neuronal metabolism of alpha-synuclein, a protein whose aggregation is believed to drive the pathogenesis in PD. Ongoing work seeks to determine the physiological and pathological implications of this LRRK2 mutation, its role in idiopathic disease, and crosstalk between LRRK2 signaling pathways and other genetic risk factors for PD.

In seeking to understand the pathological consequences of the widely reported mitochondrial Complex-1 dysfunction in sporadic PD, the LaVoie lab utilizes a combination of novel cell culture and animal models deficient in various genes critical to mitochondrial function to examine the primary pathological events that follow mitochondrial disturbance. In addition, we are uncovering novel mechanisms to improve mitochondrial function in the hopes to identify opportunities slow or halt disease progression in patients.