Research Grant Recipient

2018

Dr. Agnes Luo

Bio

Dr. Agnes Luo is an associate professor in the Department of Molecular Genetics, Biochemistry and Microbiology at University of Cincinnati where her laboratory studies the mechanisms of neuronal death and repair in neurological diseases such as stroke, Parkinson’s disease and traumatic brain injury (TBI). Dr. Luo received her Ph.D degree from University of Rochester and received her post-doctoral training at NIH. In 2011, Dr. Luo joined Case Western Reserve University as Assistant Professor and started the Neuroprotection and Neuroregeneration research program at the Department of Neurological Surgery at CWRU. She recently joined the Department of Molecular Genetics at University of Cincinnati (2018). Research in her lab focuses on investigating the key genes/pathways that determines the survival of neurons in neurodegenerative diseases including Parkinson’s disease and stroke (Neuroprotection). Her research group also focuses on understanding the role of neural progenitor cells (NPCs) and reactive astrocytes that acquire stem cell properties during brain injury recovery (Neuroregeneration). The long-term goal of her research is to identify key molecular pathways and pharmacological molecules that modulate these pathways to promote neuroprotection (early intervention) or enhance neuroregeneration (late intervention). Utilizing combined inducible cell-type specific or activity-dependent gene deletion animal models with pharmacological manipulations of molecular pathways, she has demonstrated that neuronal specific deletion of p53 gene leads to enhanced survival of cortical and hippocampal neurons in stroke models without affecting the process of astrogliosis, suggesting a neuronal specific role of p53 gene during pathological events. Her group were the first group demonstrated that delayed pharmacological inhibition of the p53 function (days after stroke) led to enhanced neurogenesis and survival of newly generated neurons as well as results in improved functions recovery in stroke animals. Her laboratory has established multiple transgenic lines that can induce gene modification in forebrain neurons, dopaminergic neurons, NPCs or reactive astrocytes after stroke or DA neurotoxicant challenge and have identified the Nurr1, VIP, BMP7, p53, and shh genes as critical molecular pathways in determining neuronal survival and neuronal repair in stroke and PD. They have also identified and validated the efficacy of small molecules (p53 inhibitor:PFT-alpha, APP inhibitor: phenserine, shh agonist: SAG) that regulate these pathways and improved the functional outcome or recovery in animal stroke models and animal PD models. Dr. Luo have been studying neuroprotection and neurorepair since 2005 and has published more than 40 papers focusing on neuroprotection and neurorepair in CNS stress including stroke and PD.

Dr. Agnes Luo

Project Narrative

Inhibition of Drp1 using a selective Drp1 peptide inhibitor for treatment of alpha-synuclein associated Parkinson’s Disease

Our long-term goal is to gain mechanistic insights of mitochondrial dysfunction into the pathogenesis of Parkinson’s disease (PD) and to identify neuroprotective strategies for preventing or reversing neuronal degeneration underlying PD. PD is one of the most common neurodegenerative disorders. The exact causes of neuronal damage are unknown, but mounting evidence indicates that a mitochondria-mediated pathway plays a key role in dopaminergic neuronal cell death in both PD patients and PD animal models. Thus, regulation of mitochondrial dynamic processes may be important mechanisms controlling neuronal survival. Proper mitochondrial function is maintained by mitochondrial fusion and fission events (mitochondrial dynamics). Dynamin-related protein (Drp1) mediates mitochondrial fission, whereas Mfn1/2 and Opa1 control mitochondrial fusion. Drp1 is upregulated/activated when neurons are stressed, leading to mitochondrial fragmentation, which causes neuronal dysfunction and death in various PD models. Inhibition of Drp1 could reverse mitochondrial dysfunction and confer neuroprotection during neuronal injury under stress conditions. Thus, Drp1-mediated mitochondrial fission impairment might be a therapeutic target for PD.

A novel selective Drp1 peptide inhibitor P110 was recently developed, which specifically interferes with Drp1/Fis1 (Mitochondrial fission 1 protein) protein-protein interaction occurring during mitochondrial fission. Our previous studies found that treatment with the P110 reduced mitochondrial fragmentation, corrected mitochondrial dysfunction and improved cell viability in cellular PD models and in MPTP induced PD mouse model with minimal effects on normal mitochondrial function. Preliminary study further showed that P110 treatment reduces alpha- synuclein-induced mitochondrial oxidative stress in an alpha synuclein (alpha-Syn) cellular model. Here, we hypothesize that inhibition of Drp1 using a selective Drp1 peptide inhibitor (P110) protects against alpha-synuclein-associated pathology in PD. An alphasynuclein overexpression genetic mouse model (Human-alpha-Syn (A53T) mouse line) will be used to test our hypothesis. The objective of this application is to use a novel approach to study the role of mitochondrial fission impairment in the progress of neurodegeneration underlying PD in a genetic mouse model carrying human PD mutation gene. We will test our central hypothesis by determining whether inhibition of Drp1 by P110 peptide treatment reduces pathological mitochondrial fission and mitochondrial dysfunction in the Hu-alpha-Syn (A53T) PD mouse model and whether inhibition of Drp1 by P110 peptide treatment reduces neuropathology and behavioral deficits in the Hu-alpha-Syn (A53T) PD mouse model. Our results will provide further insights into the role of mitochondrial dynamics on α-synuclein-associated neuropathology. Further, development of peptide regulators by selectively targeting pathological mitochondrial fission has the potential for future clinical translation for neurological diseases characterized by impaired mitochondrial functions including PD.