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Matthew LaVoie, PhD
Associate Scientist, Brigham and Women's Hospital
Associate Professor of Neurology, Harvard Medical School

Brigham and Women's Hospital
Department of Neurology
75 Francis Street
Boston, MA 02115

Research Location: Harvard Institute of Medicine


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Research Narrative:

The overall goal of the LaVoie lab is to elucidate the early molecular events that are responsible for the diverse pathology associated with 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 PD can provide valuable insight, as well as maintaining a focus on aspects of the far more common sporadic form of the disease. 

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 a homeostatic or pro-survival function of parkin influencing 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, and ongoing work seeks to determine the physiological and pathological implications of this unique subcellular localization.

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 models deficient in various genes critical to mitochondrial function to examine the primary pathological events that follow mitochondrial disturbance.

 


Education:
University of Pittsburgh, 2000, PhD

Honors/Awards:
Smith Family Award for Excellence in Biomedical Research
Excellence in Tutorial Facilitation (Teaching), Harvard Medical School (2008 and 2011)
Junior Scholar Award - World Parkinson's Congress
Career Development Award (K01) - NIA
Roberto Cornelli Memorial Award, 8th International Conference for Alzheimer’s and Parkinson's Disease

Publications (Pulled from Harvard Catalyst Profiles):

1. Amin P, Florez M, Najafov A, Pan H, Geng J, Ofengeim D, Dziedzic SA, Wang H, Barrett VJ, Ito Y, LaVoie MJ, Yuan J. Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFa-mediated apoptosis. Proc Natl Acad Sci U S A. 2018 06 26; 115(26):E5944-E5953.

2. Schapansky J, Khasnavis S, DeAndrade MP, Nardozzi JD, Falkson SR, Boyd JD, Sanderson JB, Bartels T, Melrose HL, LaVoie MJ. Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble a-synuclein in neurons. Neurobiol Dis. 2018 03; 111:26-35.

3. Shlevkov E, Kramer T, Schapansky J, LaVoie MJ, Schwarz TL. Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. Proc Natl Acad Sci U S A. 2016 10 11; 113(41):E6097-E6106.

4. Charan RA, LaVoie MJ. Pathologic and therapeutic implications for the cell biology of parkin. Mol Cell Neurosci. 2015 May; 66(Pt A):62-71.

5. LaVoie MJ. Career building as a neuroscientist at a research hospital. Ann Neurol. 2015 Mar; 77(3):367-70.

6. Schapansky J, Nardozzi JD, LaVoie MJ. The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease. Neuroscience. 2015 Aug 27; 302:74-88.

7. Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014 Sep 01; 206(5):655-70.

8. Renella R, Schlehe JS, Selkoe DJ, Williams DA, LaVoie MJ. Genetic deletion of the GATA1-regulated protein a-synuclein reduces oxidative stress and nitric oxide synthase levels in mature erythrocytes. Am J Hematol. 2014 Oct; 89(10):974-7.

9. Charan RA, Johnson BN, Zaganelli S, Nardozzi JD, LaVoie MJ. Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin. Cell Death Dis. 2014 Jul 03; 5:e1313.

10. Schapansky J, Nardozzi JD, Felizia F, LaVoie MJ. Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet. 2014 Aug 15; 23(16):4201-14.