Alpha-synuclein is a major protein component of Lewy bodies, a cardinal feature of the degeneratingParkinsonian brain. Alpha-synuclein has been demonstrated to intercalate into lipid membranes viaformation of an alpha helical structure in its N-terminal end. We recently demonstrated that either incubationof recombinant A53T mutant alpha-synuclein protein with mitochondria isolated from immortalized midbrainderiveddopaminergic neurons or following A53T expression within dopaminergic cells either in culture or intransgenic animals, the protein localizes to the inner mitochondria! membrane (IMM) in the form ofoligomers. Mitochondrial localization may be due to A53T's inability to undergo serine 129 (ser-129)phosphorylation as this event, which can be induced by oxidative stress, drives the wildtype protein towardscytoplasmic localization and oligomerization. Localization of A53T to the IMM is accompanied by decreasedmitochondrial membrane potential (MMP) and increased mitochondrial autophagy (mitophagy). Decreases inMMP has been shown by others to influence the mitochondrial fission-fusion rate, driving mitochondriatowards mitophagy.
In aim #1 of this grant application, we propose to: (1) Assess the ability of alphasynucleinser-129 phosphorylation to determine its subcellular localization and oligomerization (selfinteraction)state with the assistance of Drs. Gibson and Hughes of Components 11 and 6, respectively,(2) Examine the impact of mitochondrial localization on mitochondrial fission-fusion ratios and mitophagywith the assistance of Dr. Nicholls of Component 11, and (3) Examine the effects of alterations in TORactivity on associated mitophagy with the assistance of Dr. Kapahi (Component 2 and co-Pi, Component9). 'Nuclear translocation of alpha-synuclein selectively into dopaminergic midbrain neurons has beendemonstrated following either its overexpression or increased oxidative stress. Nuclear translocation mayalso be dependent upon the protein's ser-129 phosphorylation state and/or its cleavage as well as its abilityto associate with dopaminergic cytoplasmic factors. Nuclear localization appears to result in neurotoxicity viaalpha-synuclein's ability to bind histones within the nucleus reducing their acetylation. Reduced histoneacetylation could impact on gene transcription.
In aim 2 of the application, we propose to assess alphasynucleinfor post-translational modifications and interactions with dopaminergic cytosolic factors associatedwith its nuclear translocation with the assistance of Drs. Gibson and Hughes of Components 11 and 6,respectively. With Dr. Ellerby as part of Component 7, we will also examine the ability of HDAC inhibitorsor specific HDAC siRNAs to protect against these effects and with Drs. Vijg and Melov as part ofComponent 5 the impact of nuclear localization of alpha synuclein on gene transcription.
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