Synucleonopathies are a group of neurodegenerative disorders that affect over 1.5 million people in the US. Multiple system atrophy (MSA) is a fatal, rapidly progressive synucleonopathy characterized by parkinsonism and oligodendroglial accumulation of ?-synuclein (?-syn). While considerable effort has been devoted at understanding the pathogenesis of Parkinson's Disease, less is known about MSA and the mechanisms through which ?-syn accumulates in oligodendroglial cells, resulting in neurodegenerative pathology, is not completely clear. One possibility is that autophagy failure could lead to ?-syn propagation from neurons to oligodendroglial cells. We recently found that in MSA microRNA (miR-101, miR-30a, miR183, miR-96) that regulate autophagy are affected. The HYPOTHESIS is that miRNA dysregulation in MSA might down-regulate autophagy, which in turn results in defective ?-syn clearance with the consequent propagation from neurons to glia. The OBJECTIVES will be to better understand the mechanisms through which alterations in autophagy- related miRNAs are involved in the pathogenesis of MSA and to evaluate the potential value of modulating miRNA's as a novel therapeutical approach for MSA. For this purpose we will utilize a combined strategy including studies in unique mixed cell cultures in chambers, transgenic mouse models of MSA and brain tissues from MSA patients from multiple sites.
The AIMS are: ONE. To investigate in mixed neuron- oligodendroglial cell cultures the mechanisms through which alterations in miRNAs might lead to ?-syn propagation into glial cells. TWO. To determine in transgenic models of MSA if modulating miRNAs that regulate autophagy ameliorate the ?-syn pathology and spreading. THREE. To analyze the regional relationship between alterations in specific miRNAs and autophagy targets in MSA. These goals are in agreement with the NINDS 2014 PD Basic Research recommendations. Finding a link between miRNA dysregulation, autophagy deficits, and ?-syn spreading will shed light on pathogenesis of MSA, and will open the door for the study of these interactions in other neurodegenerative disorders. These studies could also lead to the development of novel therapeutical strategies for MSA.

Public Health Relevance

Synucleonopathies such as multiple system atrophy (MSA) affect over 1 million in the US. For this proposal we will investigate how alterations in autophagy-related miRNAs are involved in the pathogenesis of ?-synuclein propagation in MSA and evaluate the value of modulating miRNAs as a novel therapeutic approach for MSA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sieber, Beth-Anne
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Valera, Elvira; Masliah, Eliezer (2018) The neuropathology of multiple system atrophy and its therapeutic implications. Auton Neurosci 211:1-6
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
Ettle, Benjamin; Kerman, Bilal E; Valera, Elvira et al. (2016) ?-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. Acta Neuropathol 132:59-75
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