Abstract
While most forms of Parkinson’s Disease (PD) are sporadic in nature, a small percentage of PD have genetic causes as first described for dominant, single base pair changes as well as duplication and triplication in the α-synuclein gene. The α-synuclein gene encodes a 140 amino acid residue protein that interacts with a variety of organelles including synaptic vesicles, lysosomes, endoplasmic reticulum/Golgi vesicles and, reported more recently, mitochondria. Here we examined the structural and functional interactions of human α-synuclein with brain mitochondria obtained from an early, pre-manifest mouse model for PD over-expressing human α-synuclein (ASOTg). The membrane potential in ASOTg brain mitochondria was decreased relative to wildtype (WT) mitochondria, while reactive oxygen species (ROS) were elevated in ASOTg brain mitochondria. No selective interaction of human α-synuclein with mitochondrial electron transport complexes cI-cV was detected. Monomeric human α-synuclein plus carboxyl terminally truncated forms were the predominant isoforms detected in ASOTg brain mitochondria by 2-dimensional PAGE (Native/SDS) and immunoblotting. Oligomers or fibrils were not detected with amyloid conformational antibodies. Mass spectrometry of human α-synuclein in both ASOTg brain mitochondria and homogenates from surgically resected human cortex demonstrated that the protein was full-length and postranslationally modified by N-terminal acetylation. Overall the study showed that accumulation of full-length, N-terminally acetylated human α-synuclein was sufficient to disrupt brain mitochondrial function in adult mice.
Highlights
The causes and cures for Parkinson’s Disease (PD) remain elusive, but many roads of investigation have led to the critical importance of the a-synuclein protein
Overexpressed Human a-Synuclein is Closely Associated with Brain Mitochondria
We examined the association of a-synuclein with the pyruvate dehydrogenase (PyD) complex, which is a soluble complex found in the mitochondrial matrix and not associated with the inner membrane
Summary
The causes and cures for Parkinson’s Disease (PD) remain elusive, but many roads of investigation have led to the critical importance of the a-synuclein protein. The a-synuclein gene encodes a 140 amino acid residue protein that is expressed ubiquitously in the brain and is enriched in presynaptic terminals [1,2]. The A53T amino acid substitution in the full-length 140 amino acid sequence of human a-synuclein was the first PD familial mutation identified, while at least two additional inherited forms with single amino acid mutations (A30P, E46K) have been identified subsequently [14]. The a-synuclein protein accumulates as insoluble fibrils in Lewy bodies in sporadic forms of PD [16] and in most inherited forms of PD including the most common forms with leucine-rich repeat kinase 2 (LRRK2) gene mutations [17]
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