2016 — 2020 |
Unni, Vivek |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Mechanisms of Neuronal Cell Death in Synucleinopathies @ Oregon Health & Science University
? DESCRIPTION (provided by applicant): Synucleinopathies are a group of clinically important, progressive neurological illnesses for which there are no approved therapies that can slow, halt or reverse progression. These diseases are defined by the presence of abnormal aggregates of the protein ?-synuclein within neurites and cell bodies, known as Lewy pathology. Lewy inclusions are found in brain regions where cell death occurs, but it is not clear how they relate to disease. Recent preliminary data in mouse models using sophisticated, new in vivo imaging approaches suggests that Lewy pathology forms out of the neuron's endogenous ?-synuclein after seeding with recombinant produced ?-synuclein fibrils. Furthermore, only neurons that develop Lewy inclusions are fated to die in these models. Critical questions remain, however, including whether human Lewy pathology is formed by similar mechanisms and if human neurons also die by similar pathways as those in fibril-seeded mouse models. In order to answer these questions, advanced electron microscopic (EM) approaches will be used. The long-term goal is to determine how Lewy inclusion-bearing cells degenerate in human disease in order to guide the development of therapies to halt this process. This proposal will test the central hypothesis that specific structural and molecular properties of Lewy inclusions drive associated neuronal cell death in fibril- seeded mouse models and humans with Parkinsonism. This will be tested in three specific aims: 1) Determine the Lewy inclusion structural & molecular characteristics that predict cell death. 2) Determine the mode of programmed cell death in Lewy inclusion-bearing neurons. 3) Test whether alteration of Lewy inclusion properties underlies aggressive forms of neurodegeneration. The proposed study will be conducted at Oregon Health & Science University in collaboration with consultants at the Mayo Clinic and the University of Pennsylvania, each with complementary expertise in EM approaches to study brain disease and the neuropathology of Parkinsonism. This K02 - Independent Scientist Award will provide the candidate with the expertise in advanced EM approaches needed to study this relationship of Lewy pathology to neurodegeneration. It will also involve a variety of structured coursework, workshops and formal advising programs in order to provide an excellent foundation for launching an independent research career. Ultimately, the knowledge gained has the potential to lead to new therapeutic strategies that target cell death in ways that treat Parkinson's disease, Dementia with Lewy Bodies and related disorders.
|
0.915 |
2017 — 2020 |
Unni, Vivek |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Neurodegeneration in Lewy Body Disorders @ Oregon Health & Science University
PROJECT SUMMARY One major obstacle to halting neurodegeneration in synucleinopathies like Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB) is a lack of understanding of why vulnerable cell populations die. Although aggregated alpha-synuclein Lewy pathology occurs within specific neurons, and their dysfunction or degeneration leads to symptoms in these diseases, how Lewy pathology itself plays a role is unclear. Recent work by the Unni lab has discovered a previously unrecognized function for the protein alpha-synuclein in repairing nuclear DNA double-strand breaks (DSB), by using newly developed in vivo multiphoton imaging techniques to study alpha-synuclein aggregation in mice. These approaches have now been extended (for the first time) to study DNA repair in living mouse brain. The unexpected function for alpha-synuclein immediately suggests an exciting new hypothesis for the role of aggregated alpha-synuclein Lewy inclusions in neurodegeneration. This central hypothesis is that in disease, alpha-synuclein protein is sequestered in cytoplasmic Lewy bodies, decreasing its nuclear DSB repair function and leading to cell death of Lewy body- containing neurons. Furthermore, it is proposed that the source of fibrillar ?-synuclein that initially seeds Lewy body formation comes from dysregulated DSB repair. The preliminary data suggest this complex interrelationship, with alpha-synuclein aggregation causing dysregulated DSB repair and vice versa. Although completely novel, this link between alpha-synuclein and DSB repair could explain previously poorly understood associations between human and mouse mutations in the DSB repair protein Ataxia-Telangiectasia Mutated and alpha-synuclein aggregation, and between specific synuclein family members and cancer (e.g. alpha- synuclein & melanoma, gamma-synuclein & breast cancer). This proposal will use a combination of advanced imaging approaches in purified, reconstituted in vitro systems, in mouse brain in vivo, and in mouse & human (PD, DLB) fixed tissue to test how alpha-synuclein mediates DSB repair (Aim 1), how loss of nuclear ?- synuclein function after cytoplasmic Lewy inclusion formation dysregulates DSB repair and contributes to neuronal cell death (Aim 2), and how dysregulated DSB repair can lead to Lewy inclusion formation (Aim 3). Overall, this project is innovative because it uses powerful, new in vivo experimental approaches to test a fundamentally new hypothesis for how alpha-synuclein aggregation into Lewy pathology is related to neurodegeneration. This contribution will be significant because it will provide a completely new set of targets for treating these debilitating neurodegenerative disorders that focuses on the DSB repair pathway, and because understanding alpha-synuclein-mediated DSB repair in detail will increase our basic science knowledge of this important biological process.
|
0.915 |