Lewy body disease (LBD) is a group of disorders characterized by alpha-synuclein (a-syn) accumulation and Parkinsonism. During the previous period, the objective was to understand the mechanisms by which alpha- synuclein (a-syn) a close homologue to a-syn blocks a-syn aggregation and might have a role in the treatment of degenerative disorders such as Alzheimer's disease (AD) and LBD. Both p-syn and antibodies against a-syn target a-syn aggregates for clearance probably via autophagy, a process of degradation and recycling of cellular constituents. Alterations in autophagy might play a role in the pathogenesis of AD and LBD, and might represent a target for treatment development. The objectives of this renewal application are: i) to gain new knowledge as to the involvement of the autophagy pathways in the mechanisms of neurodegeneration in LBD, ii) to develop new experimental therapies for LBD by targeting the autophagy pathways and iii) to better understand the involvement of the autophagy pathways in the mechanisms of a- syn clearance mediated by immunotherapy. We propose the following Aims:
AIM 1. Characterize in vivo the contribution of selected molecular components of the autophagy pathway to the pathogenesis of LBD.
AIM 2. Investigate in in vivo models of alpha-synucleinopathy the therapeutic and neuroprotective effects of activators of the autophagy pathway.
AIM 3. Better understand the cellular mechanisms involved in the clearance of toxic a-syn aggregates via specific antibodies.
AIM 4. Determine in immunized animals, the contribution of autophagy to the molecular mechanisms involved in a-syn clearance. a-Syn transgenic mice will be crossed with mice either deficient in or transgenic for components of the autophagy pathway (e.g. Beclinl, LAMP2, mTor). Mice will be treated with stimulators of autophagy (rapamycin, immunotherapy) and analyzed behaviorally, biochemically and neuropathologically. Studies will be complemented with primary neuronal cultures treated with lentiviral vectors and analyzed for markers of autophagy. Better understanding the autophagic pathways involved in a-syn clearance is of central importance toward elucidating the pathogenesis of LBD and developing new treatments for these conditions. Thus, enhancing autophagy and lysosomal degradation of a-syn may represent a promising therapeutic strategy for the treatment not only for LBD but also for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG018440-10
Application #
7880153
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Buckholtz, Neil
Project Start
2000-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2010
Total Cost
$291,477
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Valera, Elvira; Masliah, Eliezer (2018) The neuropathology of multiple system atrophy and its therapeutic implications. Auton Neurosci 211:1-6
Spencer, Brian; Brüschweiler, Sven; Sealey-Cardona, Marco et al. (2018) Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders. Acta Neuropathol 136:69-87
Chen, Xu-Qiao; Fang, Fang; Florio, Jazmin B et al. (2018) T-complex protein 1-ring complex enhances retrograde axonal transport by modulating tau phosphorylation. Traffic 19:840-853
Ngolab, Jennifer; Trinh, Ivy; Rockenstein, Edward et al. (2017) Brain-derived exosomes from dementia with Lewy bodies propagate ?-synuclein pathology. Acta Neuropathol Commun 5:46
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
Adamowicz, David H; Roy, Subhojit; Salmon, David P et al. (2017) Hippocampal ?-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology. J Neurosci 37:1675-1684
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
El-Agnaf, Omar; Overk, Cassia; Rockenstein, Edward et al. (2017) Differential effects of immunotherapy with antibodies targeting ?-synuclein oligomers and fibrils in a transgenic model of synucleinopathy. Neurobiol Dis 104:85-96
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
Ihse, Elisabet; Yamakado, Hodaka; van Wijk, Xander M et al. (2017) Cellular internalization of alpha-synuclein aggregates by cell surface heparan sulfate depends on aggregate conformation and cell type. Sci Rep 7:9008

Showing the most recent 10 out of 199 publications