Matthew J LaVoie

Matthew J LaVoie, PhD

Fixel Family Professor Of Neurology, Co-Director Center Of Translational Research In Neurodegenerative Disease, Associate Chair For Research-Neurology

Department: MD-NEUROLOGY-MOVEMENT DISORDER
Business Phone: (352) 273-5579
Business Email: mlavoie@ufl.edu

Research Profile

The overall goal of the LaVoie lab is to elucidate the earliest molecular events responsible for adult onset neurodegenerative diseases. We approach these devastating disorders from both the perspective that specific inherited gene mutations linked to familial forms 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 Parkinson’s disease 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.

Open Researcher and Contributor ID (ORCID)

0000-0002-2583-1578

Areas of Interest
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis
  • Huntington’s Disease
  • Lewy Body Dementia
  • Parkinson’s disease

Publications

2020
Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation.
Neuron. 107(5):891-908.e8 [DOI] 10.1016/j.neuron.2020.06.021. [PMID] 32681824.
2020
Lysosome and Inflammatory Defects in GBA1-Mutant Astrocytes Are Normalized by LRRK2 Inhibition.
Movement disorders : official journal of the Movement Disorder Society. 35(5):760-773 [DOI] 10.1002/mds.27994. [PMID] 32034799.
2020
LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons.
Frontiers in neuroscience. 14 [DOI] 10.3389/fnins.2020.00442. [PMID] 32499675.
2018
Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis.
Proceedings of the National Academy of Sciences of the United States of America. 115(26):E5944-E5953 [DOI] 10.1073/pnas.1806973115. [PMID] 29891719.
2018
Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons.
Neurobiology of disease. 111:26-35 [DOI] 10.1016/j.nbd.2017.12.005. [PMID] 29246723.
2016
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Autophagy. 12(1):1-222 [DOI] 10.1080/15548627.2015.1100356. [PMID] 26799652.
2016
Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility.
Proceedings of the National Academy of Sciences of the United States of America. 113(41):E6097-E6106 [PMID] 27679849.
View on: PubMed
2015
Career building as a neuroscientist at a research hospital.
Annals of neurology. 77(3):367-70 [DOI] 10.1002/ana.24344. [PMID] 25561402.
2015
Pathologic and therapeutic implications for the cell biology of parkin.
Molecular and cellular neurosciences. 66(Pt A):62-71 [DOI] 10.1016/j.mcn.2015.02.008. [PMID] 25697646.
2015
The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease.
Neuroscience. 302:74-88 [DOI] 10.1016/j.neuroscience.2014.09.049. [PMID] 25284317.
2014
Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin.
The Journal of cell biology. 206(5):655-70 [DOI] 10.1083/jcb.201401070. [PMID] 25154397.
2014
Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy.
Human molecular genetics. 23(16):4201-14 [DOI] 10.1093/hmg/ddu138. [PMID] 24682598.
2014
Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin.
Cell death & disease. 5 [DOI] 10.1038/cddis.2014.278. [PMID] 24991765.
2014
Genetic deletion of the GATA1-regulated protein α-synuclein reduces oxidative stress and nitric oxide synthase levels in mature erythrocytes.
American journal of hematology. 89(10):974-7 [DOI] 10.1002/ajh.23796. [PMID] 25043722.
2013
The mitochondrial disease associated protein Ndufaf2 is dispensable for Complex-1 assembly but critical for the regulation of oxidative stress.
Neurobiology of disease. 58:57-67 [DOI] 10.1016/j.nbd.2013.05.007. [PMID] 23702311.
2012
Recognizing the cooperative and independent mitochondrial functions of Parkin and PINK1.
Cell cycle (Georgetown, Tex.). 11(15):2775-6 [DOI] 10.4161/cc.21261. [PMID] 22801534.
2012
The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax.
Proceedings of the National Academy of Sciences of the United States of America. 109(16):6283-8 [DOI] 10.1073/pnas.1113248109. [PMID] 22460798.
2011
Proteostasis and movement disorders: Parkinson’s disease and amyotrophic lateral sclerosis.
Cold Spring Harbor perspectives in biology. 3(10) [DOI] 10.1101/cshperspect.a007500. [PMID] 21844169.
2011
Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures.
Journal of neural transmission (Vienna, Austria : 1996). 118(5):795-808 [DOI] 10.1007/s00702-011-0653-2. [PMID] 21552986.
2011
PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility.
Cell. 147(4):893-906 [DOI] 10.1016/j.cell.2011.10.018. [PMID] 22078885.
2010
Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates.
The Journal of biological chemistry. 285(15):11378-91 [DOI] 10.1074/jbc.M109.088815. [PMID] 20145246.
2010
Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation.
Biochemistry. 49(26):5511-23 [DOI] 10.1021/bi100157u. [PMID] 20515039.
2009
Evidence that alpha-synuclein does not inhibit phospholipase D.
Biochemistry. 48(5):1077-83 [DOI] 10.1021/bi801871h. [PMID] 19146388.
2009
Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson’s disease.
Human molecular genetics. 18(22):4390-404 [DOI] 10.1093/hmg/ddp394. [PMID] 19692353.
2009
Lipidomic profiling in mouse brain reveals differences between ages and genders, with smaller changes associated with alpha-synuclein genotype.
Journal of neurochemistry. 111(1):15-25 [DOI] 10.1111/j.1471-4159.2009.06290.x. [PMID] 19627450.
2009
Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release.
Human molecular genetics. 18(22):4317-28 [DOI] 10.1093/hmg/ddp384. [PMID] 19679562.
2007
The effects of oxidative stress on parkin and other E3 ligases.
Journal of neurochemistry. 103(6):2354-68 [PMID] 17883392.
View on: PubMed
2005
Dopamine covalently modifies and functionally inactivates parkin.
Nature medicine. 11(11):1214-21 [PMID] 16227987.
View on: PubMed
2005
gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site.
The Journal of biological chemistry. 280(51):41987-96 [PMID] 16236717.
View on: PubMed
2004
Purification and characterization of the human gamma-secretase complex.
Biochemistry. 43(30):9774-89 [PMID] 15274632.
View on: PubMed
2004
Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity.
Experimental neurology. 187(1):47-57 [PMID] 15081587.
View on: PubMed
2004
Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex.
Biochemistry. 43(2):323-33 [PMID] 14717586.
View on: PubMed
2004
Dimerization of Parkinson’s disease-causing DJ-1 and formation of high molecular weight complexes in human brain.
Molecular and cellular neurosciences. 27(3):236-46 [PMID] 15519239.
View on: PubMed
2003
Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin.
The Journal of biological chemistry. 278(39):37213-22 [PMID] 12857757.
View on: PubMed
2003
Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates.
Neurobiology of disease. 14(2):194-204 [PMID] 14572442.
View on: PubMed
2003
gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins.
Biochemistry. 42(22):6664-73 [PMID] 12779321.
View on: PubMed
2003
Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.
Proceedings of the National Academy of Sciences of the United States of America. 100(11):6382-7 [PMID] 12740439.
View on: PubMed
2003
The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments.
The Journal of biological chemistry. 278(36):34427-37 [PMID] 12826675.
View on: PubMed
2002
Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation.
The Journal of biological chemistry. 277(38):35113-7 [PMID] 12130643.
View on: PubMed
1999
Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 19(4):1484-91 [PMID] 9952424.
View on: PubMed
1999
Peroxynitrite- and nitrite-induced oxidation of dopamine: implications for nitric oxide in dopaminergic cell loss.
Journal of neurochemistry. 73(6):2546-54 [PMID] 10582617.
View on: PubMed

Grants

Jul 2020 ACTIVE
PATHOLOGIC LRRK2 SIGNALING IN FAMILIAL AND IDIOPATHIC PARKINSON'S DISEASE
Role: Principal Investigator
Funding: NATL INST OF HLTH NINDS
May 2020 ACTIVE
Role of Parkin in Familial and Idiopathic Parkinson's Disease
Role: Principal Investigator
Funding: NATL INST OF HLTH NINDS

Education

PhD in Neuroscience
2000 · University of Pittsburgh
BA/BS in Biology/Psychology
1995 · Rutgers College

Contact Details

Phones:
Business:
(352) 273-5579
Emails:
Business:
mlavoie@ufl.edu
Administrative Specialist III: