A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration.
Several neurodegenerative diseases are typified by intraneuronal alpha-synuclein deposits, synaptic dysfunction, and dementia. While even modest alpha-synuclein elevations can be pathologic, the precise cascade of events induced by excessive alpha-synuclein and eventually culminating in synaptotoxicity is unclear. To elucidate this, we developed a quantitative model system to evaluate evolving alpha-synuclein-induced pathologic events with high spatial and temporal resolution, using cultured neurons from brains of transgenic mice overexpressing fluorescent-human-alpha-synuclein. Transgenic alpha-synuclein was pathologically altered over time and overexpressing neurons showed striking neurotransmitter release deficits and enlarged synaptic vesicles; a phenotype reminiscent of previous animal models lacking critical presynaptic proteins. Indeed, several endogenous presynaptic proteins involved in exocytosis and endocytosis were undetectable in a subset of transgenic boutons ("vacant synapses") with diminished levels in the remainder, suggesting that such diminutions were triggering the overall synaptic pathology. Similar synaptic protein alterations were also retrospectively seen in human pathologic brains, highlighting potential relevance to human disease. Collectively the data suggest a previously unknown cascade of events where pathologic alpha-synuclein leads to a loss of a number of critical presynaptic proteins, thereby inducing functional synaptic deficits.
Scott
David A
DA
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
Tabarean
Iustin
I
Tang
Yong
Y
Cartier
Anna
A
Masliah
Eliezer
E
Roy
Subhojit
S
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007381:Intermediate Filament Proteins / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010447:Peptide Hydrolases / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C092350:FM 4-64; D007381:Intermediate Filament Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D010982:Platelet-Derived Growth Factor; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; C430456:desmuslin; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; D010447:Peptide Hydrolases