Accumulation of Phosphorylated α-Synuclein in Aging Human Brain

262

215

Recent studies suggest that excitotoxicity may contribute to neuronal damage in neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. Activated microglia have been observed around degenerative neurons in these diseases, and they are thought to act as effector cells in the degeneration of neural cells in the central nervous system. Neuritic beading, focal bead-like swellings in the dendrites and axons, is a neuropathological sign in epilepsy, trauma, ischemia, aging, and neurodegenerative diseases. Previous reports showed that neuritic beading is induced by various stimuli including glutamate or nitric oxide and is a neuronal response to harmful stimuli. However, the precise physiologic significance of neuritic beading is unclear. We provide evidence that neuritic beading induced by activated microglia is a feature of neuronal cell dysfunction toward neuronal death, and the neurotoxicity of activated microglia is mediated through N-methyl-D-aspartate (NMDA) receptor signaling. Neuritic beading occurred concordant with a rapid drop in intracellular ATP levels and preceded neuronal death. The actual neurite beads consisted of collapsed cytoskeletal proteins and motor proteins arising from impaired neuronal transport secondary to cellular energy loss. The drop in intracellular ATP levels was because of the inhibition of mitochondrial respiratory chain complex IV activity downstream of NMDA receptor signaling. Blockage of NMDA receptors nearly completely abrogated mitochondrial dysfunction and neurotoxicity. Thus, neuritic beading induced by activated microglia occurs through NMDA receptor signaling and represents neuronal cell dysfunction preceding neuronal death. Blockage of NMDA receptors may be an effective therapeutic approach for neurodegenerative diseases.

Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

Neuritic Beading Induced by Activated Microglia Is an Early Feature of Neuronal Dysfunction Toward Neuronal Death by Inhibition of Mitochondrial Respiration and Axonal Transport

Takeuchi

Mizuno

Zhang

et al. 2005

262

215

“…Of these, however, Ser-129-targeted phosphorylation is preferentially and consistently up-regulated in PD and related synucleinopathies (10,12,(32)(33)(34)(35)(36). More than 90% of ␣-syn is phosphorylated on Ser-129 in LB as compared with less than 5% in unaffected brains, suggesting that phosphorylation may influence its rate of aggregation and toxicity or its overall stability.…”

Section: Discussionmentioning

confidence: 99%

Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization

Samuel

Flavin²,

Iqbal

et al. 2016

144

Although trace levels of phosphorylated ␣-synuclein (␣-syn) are detectable in normal brains, nearly all ␣-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on ␣-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of ␣-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated ␣-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated ␣-syn isoforms were detected earlier, although the fibrils remained phosphatase-and protease-sensitive. Membrane binding of ␣-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT ␣-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P ␣-syn binding was greatly increased, and A53T ␣-syn was slightly lower, implicating distal effects of the carboxyl-on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of ␣-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated ␣-syn isoforms, a potential means for misfolded extracellular or lumenal ␣-syn to access cytosolic ␣-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of ␣-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of ␣-syn misfolding.

“…␣-Synuclein was detected with a mouse monoclonal antibody Syn211 (32), and ␣-synuclein phosphorylated at serine 129 was detected with a mouse monoclonal antibody pSyn#64 (33).…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of α-Synuclein Protein at Ser-129 Reduces Neuronal Dysfunction by Lowering Its Membrane Binding Property in Caenorhabditis elegans

Kuwahara

Tonegawa

Ito

et al. 2012

Self Cite

Background:The pathogenic role of phosphorylation of ␣-synuclein in Parkinson disease remains unclear. Results: Ser-129-substituted ␣-synuclein was expressed in transgenic C. elegans. Nonphosphorylatable (S129A) ␣-synuclein showed severe defects. The level of membrane-bound ␣-synuclein was increased in S129A-␣-synuclein. Conclusion: Ser-129 phosphorylation of ␣-synuclein attenuates neuronal dysfunction and downstream stress response by lowering the membrane binding property. Significance: Phosphorylation of ␣-synuclein is protective against neurotoxicity.