Alpha-synuclein abnormalities are implicated in a number of neurodegenerative diseases;including Parkinson's disease (PD), Lewy Body Dementia (LBD), and Multiple Systems Atrophy (MSA). Because alpha-synuclein aggregates in neurons (PD, LBD) and/or oligodendrocytes (MSA) are prominent pathological features of these diseases, they are categorized as alpha-synucleinopathies. Collectively, alpha-synucleinopathies represent the second most common late-onset neurodegenerative disease, next to Alzheimer's disease (AD). While there are no effective therapies that can slow or stop the progression of neurodegeneration associated with alpha-synucleinopathies, availability of multiple transgenic mouse models of various alpha-synucleinopathies allows us to better understand the genesis of alpha-synuclein abnormalities in vivo and mechanisms of neurodegeneration in brain. These efforts will likely lead to identifying novel therapeutic targets for alpha-synucleinopathies. Presence of intracellular alpha-synuclein aggregates in alpha-synucleinopathy suggest that some aspect of protein degradation/quality control is dysfunctional in the diseases. Consistent with this view, we found that neurodegeneration in cellular and transgenic mouse models of neuronal alpha-synucleinopathy is associated with chronic Endoplasmic Plasmic Reticulum Stress (ERS) with abnormal Unfolded Protein Response (UPR). Our studies indicate that ERS is initiated by translocation and aggregation of alpha-synuclein within the ER. More important, pharmacological treatment with an anti-ERS compound, Salubrinal, significantly delays disease manifestation in rodent model of neuronal alpha-synucleinopathy. These results suggest that ERS response pathway, particularly modulation of phospho-eIF2alpha levels could represent a novel therapeutic target for PD and other alpha-synucleinopathies. However, because of compounds such as Salubrinal may have unknown off-target effects in vivo, a rigorous validation the phospho-eIF2alpha as therapeutic target at molecular levels are needed. Further, it is not clear if all alpha-synucleinopathies shar common neurodegenerative mechanisms. With these issues in mind, we propose following studies. First, we will study whether chronic ERS is a general feature of alpha-synucleinopathy by studying ERS in both neuronal and glial alpha-synucleinopathies (PD, LBD, MSA). Second, we will determine if aging related factors, such as oxidative stress/mitochondrial dysfunction, promotes ER accumulation of alpha-synuclein oligomers. Finally, we will determine whether the genetic alterations in components of the Perk/eIF2alpha arm of the ERS have predictable effects on alpha-synuclein dependent neurodegeneration. These studies will establish the value of ER stress pathway, particularly Perk/eIF2alpha components, as targets for development of novel therapies for PD.

Public Health Relevance

Currently, there are no effective therapies for slowing or reversing progressive nature of PD. The proposed studies will use novel models of alpha-synuclein dependent neurodegeneration to rigorously validate ER stress pathways as a potential target for therapy development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Sutherland, Margaret L
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University of Minnesota Twin Cities
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