A Pathologic Cascade Leading to Synaptic Dysfunction in -Synuclein-Induced Neurodegeneration

• DOI: 10.1523/jneurosci.1091-10.2010
• Publication Date: 2010-06-16T20:30:32Z
• Authors: D. A. Scott; I. Tabarean; Y. Tang; A. Cartier; E. Masliah; S. Roy
• Keywords: Aged, 80 and over; 0301 basic medicine; Dose-Response Relationship, Drug; Green Fluorescent Proteins; Intracellular Signaling Peptides and Proteins; Excitatory Postsynaptic Potentials; Membrane Proteins; Mice, Transgenic; Hippocampus; Membrane Potentials; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals, Newborn; Intermediate Filament Proteins; Animals; Humans; Dementia; Disks Large Homolog 4 Protein; Guanylate Kinases; Cells, Cultured; Aged

Several neurodegenerative diseases are typified by intraneuronal α-synuclein deposits, synaptic dysfunction, and dementia. While even modest elevations can be pathologic, the precise cascade of events induced excessive eventually culminating in synaptotoxicity is unclear. To elucidate this, we developed a quantitative model system to evaluate evolving α-synuclein-induced pathologic with high spatial temporal resolution, using cultured neurons from brains transgenic mice overexpressing fluorescent-human-α-synuclein. Transgenic was pathologically altered over time showed striking neurotransmitter release deficits enlarged vesicles; phenotype reminiscent previous animal models lacking critical presynaptic proteins. Indeed, several endogenous proteins involved exocytosis endocytosis were undetectable subset boutons (“vacant synapses”) diminished levels remainder, suggesting that such diminutions triggering overall pathology. Similar protein alterations also retrospectively seen human brains, highlighting potential relevance disease. Collectively data suggest previously unknown where leads loss number proteins, thereby inducing functional deficits.