We will address the hypothesis that different neurodegenerative diseases are caused by the accumulation of distinct proteins with pathogenic conformations (proteopathies). These disorders are a complex biomedical, behavioral, and social problem as they are increasing in frequency, cause major disability, and remain largely untreatable. If the ways in which different proteins damage nerve cells overlap, treatments may be developed to prevent and reverse more than one of these conditions. We have assembled five interactive projects and four essential cores to study the mechanisms by which proteins associated with Alzheimer's, Parkinson's, or Huntington's disease impair neuronal function and survival. The program is multidisciplinary and relies on state-of the-art technology, including X-ray crystallography, robotic microscopy, transgenic and gene-targeted mouse models, cellular biology, neuropathology, and behavioral neuroscience. Project 1, """"""""Polyglutamine Conformation and Neurodegeneration,"""""""" aims to differentiate whether visible aggregates or other conformational states of mutant huntingtin are responsible for Huntington's disease-related neurodegeneration. Project 2, """"""""Protein Structure in Apolipoprotein E4-associated Neurodegeneration,"""""""" will test whether the Alzheimer's disease-promoting effect of apolipoprotein E4 depends on the conformation and stability of this molecule. Project 3, """"""""Apolipoprotein E in Neurobiology: Cellular Mechanisms,"""""""" will examine whether apolipoprotein E4 promotes Alzheimer's disease-like pathology through amyloid beta peptide (Abeta)-dependent pathways or via independent mechanisms. Project 4, """"""""Causes and Consequences of alpha-Synuclein Aggregation,"""""""" will assess whether pathogenic interactions between Abeta and alpha-synuclein could contribute to the development of Parkinson's disease and other Lewy body diseases. Project 5, """"""""Mechanisms of AbetaD-induced Neuronal Deficits,"""""""" will analyze the molecular cascades that link the formation of neurotoxic Abeta assemblies to Alzheimer's disease-related cognitive decline and test whether these cascades can be modulated by apolipoprotein E isoforms and alpha-synuclein. The Cores (A: Administrative; B: Tissue Culture; C: Animal; D: Neuropathology/Imaging) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG022074-02
Application #
6755910
Study Section
Special Emphasis Panel (ZAG1-ZIJ-3 (J2))
Program Officer
Snyder, Stephen D
Project Start
2003-06-15
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$2,299,012
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Valera, Elvira; Spencer, Brian; Mott, Jennifer et al. (2017) MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci 10:329
Valera, Elvira; Spencer, Brian; Fields, Jerel A et al. (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 5:2
Overk, Cassia; Masliah, Eliezer (2017) Perspective on the calcium dyshomeostasis hypothesis in the pathogenesis of selective neuronal degeneration in animal models of Alzheimer's disease. Alzheimers Dement 13:183-185
Spencer, Brian; Potkar, Rewati; Metcalf, Jeff et al. (2016) Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease. J Biol Chem 291:1905-20
Valera, E; Monzio Compagnoni, G; Masliah, E (2016) Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy. Neuropathol Appl Neurobiol 42:95-106
Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-?, ?-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous ?-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci 36:7971-84
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352

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