Michael Lee, Ph.D.

Professor, Department of Neuroscience

ITN Scholar, Center for Neurodegenerative Disease, Institute for Translational Neuroscience (http://itn.umn.edu/)

E-MAIL: mklee@umn.edu

Research Interests:

My group is committed to using genetic, cell biological and neuropathological approaches to accurately model and study in vivo mechanisms of human neurodegenerative diseases, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD).   While most cases of AD and PD are “sporadic”, the key assumption is that genetic lesions that cause classic forms of the relevant neurodegenerative diseases will cause neural abnormalities that are common between the genetic and sporadic forms of the disease.  When used in conjunction with careful analysis of human subjects and cellular models, we will be able to define mechanisms that are directly relevant to the pathogenesis and identify possible targets for therapeutic intervention.  In addition, neuronal abnormalities associated with neurodegenerative diseases are complex and require interdisciplinary effort. To aid in our effort, my lab uses state of the art quantitative neuropathology (MBF Stereology, HALO), biochemistry and proteomics, and cellular and spatial transcriptomic analysis (snRNAseq, RNAscope, GeoMx, CosMx).  Finally, I am actively collaborating with translational and basic scientists locally, nationally, and internationally to define novel disease relevant neurobiological/neurophysiological pathways and develop novel therapies. 

Alzheimer’s Disease (AD)

While AD is characterized by progressive neurodegeneration, in vivo mechanisms of neurodegeneration in AD are poorly defined. This gap in our knowledge is a significant impediment in the development of disease modifying therapies for AD. Specifically, the lack of AD-relevant progressive neurodegeneration as outcome measures in preclinical studies using AD mouse models contributes to the general failure of preclinical studies to translate into successful therapies for humans.  My laboratory was first to show that the degeneration of monoaminergic (MAergic) neurons (5-HT, NE, and DA neurons in VTA) seen in AD cases is recapitulated in transgenic (Tg) mouse models of amyloid pathology. We are using this system to understand mechanisms of neurodegeneration in AD and to determine if preclinical interventions can attenuate the progressive neurodegeneration in AD. 

We are currently studying both cell autonomous (Tau, a-Syn, Prp, Fyn, etc) and non-cell autonomous (Ab species, inflammation, etc) factors implicated in AD.  We are finding that some factors are involved in memory deficits but NOT in neurodegeneration.  Moreover, we are incorporating progressive neurodegeneration in our preclinical evaluation of AD therapies.  We are using this model to study the role of oxidative stress mechanisms (Nrf2/Bach1; Gloxylase-1/Glycation; Sulfation), proteostatic balance, inflammation, and senescence in AD.  In addition to using genetic manipulations, we are using novel “candidate therapeutic compounds” to study the disease relevance of these pathways.   

Parkinson’s Disease (PD) and Lewy Body Dementia (LBD) 

            Genetic and biochemical abnormalities of α-synuclein (αS) are directly relevant to the pathogenesis of PD.   My group has contributed to the field by generating a human αS Tg (TgaS) mouse model of α-synucleinopathy, characterizing the pathological abnormalities associated with the disease, and characterizing the normal/abnormal cell biology of α-Syn.  We use combination of constitutive and conditional aS Tg mice, aS preformed fibril (pff) inoculation model, and conditional knockout mice to define pathways that are relevant to in vivo biology.

Abnormal cellular degradation systems in αSyn-dependent neurodegeneration:  The mutant human TgaS model developed in my lab is a widely used to study the link between aS aggregation and neurodegeneration in vivo. Neuropathology in the TgαS mice is associated with ubiquitin-proteasome stress, ER-stress/Unfolded protein response (ERS/UPR), autophagic/lysosomal defects and oxidative stress (mitochondrial dysfunction, GSH depletion, and c-Abl activation).   We are using combinations mouse genetics, biochemical studies and cell biological analysis to fully define disease relevant pathway.  Recently, we have found that a-synucleinopathy is linked to c-Abl activation that led to deficits in autophagy via Mdm2-p53 axis.   

The pathways implicated in a-synucleinopathy is also seen with aging, which is the greatest risk factor of PD.  Thus, we are defining the pathogenic relationship between senescence, a major driver of aging, and PD.  This effort is part of large international consortium of researcher effort funded by Aligning Science Across Parkinson’s (ASAP) (https://parkinsonsroadmap.org/#). 

Mechanisms of aSyn-dependent cognitive deficits:  While PD is commonly associated with motor deficits from the loss of dopaminergic (DAergic) neurons in the SNpc, DA-independent non-motor dysfunctions, particularly memory problems, are known to have greater negative impact on patient quality of life in PD and related Dementia with Lewy Bodies (DLB).  Current view is that abnormalities in aS is pathogenically linked to both motor and non-motor abnormalities in PD.  We made a novel discovery that mutant aS causes postsynaptic deficit and memory deficits mediated by tau. We are using combination of genetic manipulations, neurophysiological approaches, and cell biological/biochemical analysis to further define molecular mechanisms of aS dependent cognitive deficits.   For example, we found that endogenous tau expression is required for cognitive deficits in TgaS model.  Significantly, neurophysiological analysis shows that loss of tau expression reverses aS dependent synaptic abnormalities in hippocampal slices and dissociated cultures. Further, studies done in collaboration with Dr. Keith Vossel (Director of Alzheimer’s Disease Center, Dept. of Neurology, UCLA) indicate that epileptic activity (or network hyperactivity) is temporally linked to development of cognitive deficits in TgaS model.   Thus, we hypothesize that dementia in DLB/PDD could be treated by antiepileptic drugs. My collaboration with Dr. Vossel also leads us to the idea of treating other “network” associated abnormalities in DLB. 

Cell Biology of a-Syn:  We are defining the cellular metabolism of normal and pathological forms of a-Syn.  My group was first to identify posttranslational C-terminal truncation of a-Syn as a normal cellular process and, similar to Ab in AD, increased levels of truncated a-Syn, which promote a-syn aggregation is associated with PD.  We are also working to define differential metabolism of a-Syn aggregates in neurons verses glial cells.  We are designing experiments to determine the in vivo pathogenic significance of differential aS processing in neural cells.

Novel Therapeutic Compounds and Approaches

            We are also developing novel therapeutic compounds.  Guanabenz (GA) is a FDA approved CNS acting antihypertensive drug that is thought to act as a2-adrenergic receptor (AR) agonist.  Working Dr. Swati More (UofM, Center for Drug Design), we have developed GA analog lacking undesirable properties of GA (hypotensive and sedation) that exhibit neuroprotective and/or analgesic activity.  We are also working with Dr. More to develop compound that will alleviate oxidative stress and/or senescence in neurodegenerative diseases.

Selected Publications:

(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine or Google Scholar, https://scholar.google.com/citations?hl=en&user=mNNSV4oAAAAJ&view_op=list_works&sortby=pubdate)

  • Nanclares C, Poynter J, Martell-Martinez HA, Vermilyea S, Araque A, Kofuji P*, Lee MK*, Covelo A*. Dysregulation of astrocytic Ca2+ signaling and gliotransmitter release in mouse models of α-synucleinopathies. Acta Neuropathol. 2023 Feb 10;. doi: 10.1007/s00401-023-02547-3. PMID: 36764943. JIF-17.1. *Co-corresponding Authors.

  • Vermilyea SC, Christensen A, Meint J, Singh B, Martell-Martínez H, Karim MR, Lee MK.  Loss of tau expression attenuates neurodegeneration associated with a-synucleinopathy. Translational Neurodegeneration. 2022, 11(34).  doi.org/10.1186/s40035-022-00309-x. JIF-9.008.

  • Kwon YI, Xie W, Zhu H, Xie J, Shinn K, Juckel N, Vince R, More SS*, Lee MK*. γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model.  Antioxidants. 2021, 10(11):1796. doi.org/10.3390/antiox10111796. JIF-6.3.      *Co-corresponding authors.

  • Karim MR, Liao EE, Kim J, Meints J, Martinez HM, Pletnikova O, Troncoso JC, and Lee MK.  a-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment.  Molecular Neurodegeneration2020, 15(1):27. PMID: 32299471. JIF-12.42

  • Singh B, Covelo A, Martell-Martínez H, Nanclares C, Sherman MA, Okematti E, Meints J, Teravskis PJ, Gallardo C, Savonenko AV, Benneyworth MA, Lesné SE, Liao D, Araque A, Lee MK. (2019) Tau is required for progressive synaptic and memory deficits in transgenic mouse model of a-synucleinopathy.  Acta Neuropathol. 2019, 138:551-574. PMID: 31168644. JIF-17.09

  • Salazar SV, Gallardo C, Kaufman AC, Herber CS, Haas LT, Robinson S, Manson JC, Lee MK, Strittmatter SM.  Conditional Deletion of Prnp Rescues Behaviroal and Synaptic Deficits after Disease onset in Transgenic Alzheimer’s Disease.      J Neurosci2017, 27:9207-9221. 2017.  JIF-6.07

  • Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK.   Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J Neurosci., 2012,  32: 3301-3305. 

  • Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, Iwatsubo T, Schneider BL, Lee MK.  Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo J Neurosci., 2012, 32: 3306-3320. This Week in Journal (TWIJ) article. 


Former Graduate Students:

Balvindar Singh (Neuroscience, University of Minnesota)

Michael Lee