2005 — 2009 |
Giasson, Benoit I |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Abnormal Dj-1 and Alpha-Synuclein in Neurodegeneration @ University of Pennsylvania
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and it shares many common features, such as aberrant protein aggregation, with a broader spectrum of neurodegenerative diseases. Despite the knowledge that the loss of specific dopaminergic neurons in the midbrain is largely responsible for many of the clinical presentations of PD, there are significant unknowns about the mechanisms that lead to neuronal death. Genetic studies have identified new mutations and gene defects that can be responsible for disease. Although familial PD is relatively rare, these genetic findings have led to critical insights toward understanding the underlying cause of disease and they may begin to define important biological pathways involving the interaction of these gene products. The identification of mutations in the alpha-synuclein gene has revealed that this protein is the major component of disease-characteristic inclusions known as Lewy bodies. Furthermore, various types of alpha-synuclein filamentous inclusions have been shown to be involved in the etiology of many neurodegenerative diseases. However, there is evidence to suggest that the formation of these mature inclusions and/or the small oligomers, which can take the appearance of "spheres", can be involved in degeneration. In this proposal, the novel (E46K) mutation in alpha-synuclein, previously identified mutants and the wild-type protein will be studied in vitro, in tissue culture paradigms and in transgenic mice to investigate the molecular interactions and mechansims that lead to the aberrant polymerization of alpha-synuclein. The role of small polymeric "sphere" compared to mature filamentous inclusions in the disease process will be assessed. Defects in the DJ-1 gene have been linked to PD or PD-like disease, and an interactive pathogenic link between DJ-1 and alpha-synuclein, perhaps involving oxidative stress mechanisms, in normal and disease state will be evaluated. These findings should provide important information as to the directions for planning for effective therapeutic approaches.
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2007 — 2011 |
Giasson, Benoit I |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Interactions of Protein Aggregation in Parkinson's Dementia @ University of Pennsylvania
Parkinson's disease (PD), is the most common neurodegenerative movement disorder, and it^.shares many common features, such as protein aggregation, with a broader spectrum of neutodegenerative diseases. PD can present with additional clinical impairments and dementia is common in PD patients. Despite the knowledge that the loss of specific dopaminergic neurons in the midbrain is largely responsible for most of the motor dysfunction in PD, there are significant unknown about the mechanism that lead to neuronal death. Although familial PD is relatively rate, the identification of mutation in the alpha-synuclein gene has lead to the discovery that this protein is the major component of disease-characteristic inclusions known as Lewy bodies and Lewy neurites. Alpha-synuclein is normally a soluble protein, but it can polymerize into 10-15 nm fibrils with specific biophysical properties known as "amyloid" to form pathological inclusions. Pathological inclusions such as intracellular neurofibrillarytangles and extracellular Abeta peptide deposits, which are characteristic of Alzheimer's diseasae, frequently present concomitantly with alpha-synyuclein aggregates. Indeed, apha-synuclein and tau inclusions can occur in the same cells, often intertwined. Alpha-synuclein has been shown to be able to act as an induceer of tau aggregation, and both proteins can enhance the ploymerization of each other once this process is initiated. However, the molecular mechanism and the physiological changes that lead to this process have not been elucidated. Test tube experiments and transgenic mice studies will be conducted to address these issues. Studies will be conducted to assess selective vulnerability and behavioral impairments in transgenic mice resulting from alpha-synuclein and tau interactions leading to the formation of pathological consequences. Aberrant physiological alterations,such as nitrative damage and hyperphosphorylation, may be involved in mediating alpha-synuclein and tau interactions and these mechanisms will be investigated. Transgenic mouse models of Abeta peptide deposits will also be used to assess possible pathological mechanisms by which these inclusions may promote alpha-synuclein aggregation. These findings shown provide important information on mechanisms and physiological changes that lead to the formaion of alpha-synuclein and tau inclusions, and may lead to insights in planning for effective therapeutic approaches.
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2014 — 2018 |
Giasson, Benoit I |
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 Aggregated Alpha-Synuclein Induction and Progression
DESCRIPTION (provided by applicant): Parkinson disease (PD) is the most common movement disorder affecting over one million people in North America alone and results in an insidious reduction in the quality of life and ability to function. A hallmark of PD is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein a-synuclein, but the presence of ?-synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that ?-synuclein amyloid pathology may spread during disease progression by a self-templating alteration in protein conformation mechanism, however other alternative and/or synergistic biological mechanisms, as supported by our data, could also lead to progression of ?-synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of ?-synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on ?-synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of ?-synuclein with unique aggregation properties, we will directly investigated that a-synuclein aggregation can spread within the central nervous system and from the periphery with specific conformational characteristics. 2) We will assess the importance of alternative biological mechanisms including perturbation of the protein network homeostasis, neuronal intermediate filament integrity, neurotoxicity and age-related changes in the induction and propagation of ?-synuclein pathology by exogenous a-synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of ?-synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.
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2017 — 2018 |
Borchelt, David R [⬀] Chakrabarty, Paramita (co-PI) [⬀] Giasson, Benoit I |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Apoe as a Modifier of Prion-Like Spread in Dementia
Title: APOE as a modifier of prion-like spread in dementia Abstract: The overall objective of this multidisciplinary project is to test the hypothesis that relative to APOE2 or APOE3, APOE4 facilitates the seeding and spread of misfolded A? and tau. Inheritance of an APOE4 allele increases the risk of developing Alzheimer's disease (AD) dramatically. Most studies suggest that the primary mechanism by which APOE genotype modulates the risk for AD is by influencing the deposition of A? peptide. However, there are studies that suggest APOE may also directly modulate the phosphorylation and misfolding of tau. Somewhat surprisingly, although the first descriptions of A? seeding in mice were reported more than 10 years ago and various human APOE models have been available for many years, there have been no studies of how APOE genotype may modulate seeding or spread of misfolded A?. Similarly, there has been no study of how APOE genotype may influence the spread of misfolded tau. We now propose three Aims to conduct a thorough and systematic assessment of how different isoforms of human APOE impact the prion-like seeding and spread of misfolded A? and tau. A component of our study will also asess whether different APOE isoforms may interact with these aggregating proteins to produce distinct strains of misfolded A? or tau. Aim 1 will determine the relative ability of APOE2, APOE3 and APOE4 to support the seeding of A? pathology, the spread of A? aggregates within the brain, and whether APOE isoforms modulates the strain characteristics of the seeded A? aggregates. Aim 2 will determine whether APOE genotype influences the spread of CNS tau pathology, and whether any observed influence in spread is potentially due to the emergence of distinct strains of misfolded tau. Aim 3 will examine whether APOE isoforms may differentially modulate A?-induced misfolding of tau. Collectively, these studies will produce a unique repertoire of animal models and provide the first assessment of whether different human APOE isoforms may be influencing that pathogenesis of AD by modulating the prion-like seeding or spread of misfolded A? and tau.
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2017 — 2018 |
Chakrabarty, Paramita [⬀] Giasson, Benoit I Hoffman, Brad E (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Immune Modulation and Cns Pathology Following Exogenous ?-Synuclein Challenge
Progressive accumulation of intracellular inclusions of ?-synuclein protein in the nervous system is a characteristic feature of Lewy Body diseases which is part of a spectrum of sporadic and hereditary neurodegenerative diseases termed ?- synucleinopathies. The definitive involvement of ?-synuclein in the etiology of these disorders was established by the findings that mutations in ?-synuclein can directly cause Lewy body dementia. Many studies suggest that the progressive spread of ?-synuclein pathology in the peripheral nervous system and the brain occurs through direct ?-synuclein transmission between cells. However, there is a major gap in our understanding of the epigenetic factors that modulate such prionoid properties of ?-synuclein. Our preliminary data suggests that ?-synuclein is an immunogenic protein and that additional factors, such as activation of cellular immunity, may contribute to the prionoid propagation of peripherally administered exogenous ?-synuclein to the CNS of mice. To provide novel insights into immune-mediated mechanisms involved in induction of CNS ?-synuclein inclusion pathology following peripheral challenge with exogenous ?-synuclein, we have assembled a team of experienced investigators with diverse and unique expertise in ?-synuclein proteostasis and neuroimmune regulation. In Aim 1, we will determine whether inflammatory preconditioning of peripheral immune milieu exacerbates induction and CNS transmission of ?-synuclein pathology following peripheral challenge with exogenous ?- synuclein fibrils. In Aim 2, we will test whether the prionoid properties of ?-synuclein fibrils is suppressed in two independent lines of immunodeficient ?-synuclein transgenic mice. Our study will inform us on the interplay between ?- synuclein seeding and propagation and cellular immunity. We expect our study to be highly translational as it will clarify 1) potential interactions between ?-synuclein and cellular immunity and further help us 2) devise preventive immunobiotherapies strategies to slow down intercellular ?-synuclein pathogenesis in the future.
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2017 — 2018 |
Giasson, Benoit I |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Pathological Spread and Outcomes of Alpha-Synuclein Mutants
Project Summary/Abstract The progressive accumulation of ?-synuclein intracellular inclusions in the nervous system is a characteristic feature of dementia with Lewy bodies and Parkinson's disease which are part of a spectrum of sporadic and hereditary neurodegenerative diseases termed ?-synucleinopathies. The definitive involvement of ?-synuclein in the etiology of these disorders was established by the findings that mutations in ?-synuclein can directly cause these neurodegenerative disorders. Many studies suggest that the progressive spread of ?-synuclein pathology in the peripheral nervous system and the brain through direct ?-synuclein interactions and transmission between cells may contribute to disease progression. However, some studies characterizing the properties of novel ?- synuclein mutants demonstrated divergent effects that are not consistent with this simple spreading mechanism. It is also important to emphasize that there is still ongoing debate as to the nature of the toxic ?-synuclein species. To provide new insights on these contentious and critical issues that will address the unique properties of disease-associated ?-synuclein mutants, we have formed a team of experienced investigators with diverse and unique expertise. In Aim 1, we will determine the inherent aggregation and neurotoxicity properties of these novel ?-synuclein mutants in vivo and compare these outcomes to the more extensively characterized ?-synuclein mutants. In Aim 2, we will test the hypothesis that in vivo prion-like seeding can differentially impact the induction and propagation of ?-synuclein inclusion pathology of disease-causal ?-synuclein mutants with unique stain-like properties. These studies will provide pivotal information regarding the neurotoxicity of abnormal forms of ?- synuclein, their impact of the induction and spread of ?-synuclein pathology and the associations with neurodegeneration.
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2018 — 2021 |
Borchelt, David R (co-PI) [⬀] Giasson, Benoit I |
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. |
Prion and Non-Prion Induction Mechanisms of Alpha-Synuclein Pathology
The presence of a-synuclein brain aggregates are a hallmark of a spectrum of neurodegenerative disorders, including Parkinson disease, Lewy body dementia and multiple system atrophy, and are associated with disease severity. Several studies suggest that this ?a-synuclein pathology may spread during disease progression by a self-templating mechanism and that nervous tissue containing aggregated a-synuclein could be a risk for disease transmission similar to prion disease. However, we recently demonstared that a non-??- synuclein factor enriched in central nervous tissue-derived white matter is sufficient to induce the progressive formation of a-synuclein inclusion pathology that can mimic prion-like transmission of a-synuclein pathology. These observations suggest the presence of a yet unidentified factor that can trigger a-synucleinopathy, similar to protein X, a putative auxiliary factor in prionopathies. Furthermore, this factor may have a pathogenic role in human disease. To resolve critical issues at the core of whether synucleinopathies should be re-classified as prion disorders and to elucidate mechanisms involved in disease progression we propose the following aims: 1) characterize the biochemical properties of the non-a-synuclein component that can trigger the progressive formation of a-synuclein, 2) determine whether a-synuclein aggregates can truely exhibit properties expected of classical prions, and 3) determine the relative prion-like transmission properties of central nervous tissue from patients with multiple system atrophy and Lewy body dementia, two phenotypically distinctive a-synucleinopathies. These highly integrated aims will provide important mechanistic and biologically relevant insights into the mechanisms and risk of pathology transmission from tissues containing a-synucleinopathies.
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