Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)–derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity

POSSIBILITIES OF COMBINATIONAL MAGNESIAL AND NEUROPROTECTOR THERAPY IN PATIENTS WITH EARLY CEREBROVASCULAR PATHOLOGY

The serum level of magnesium was evaluated in 232 teenagers and adolescents with early cerebrovascular diseases aged 16–21 years. In cases of magnesium deficiency, monotherapy with complex magnesium medication is an effective treatment both for concurrent magnesium deficiency and for early forms of cerebrovascular pathology with different patterns of vascular response (hyper_ and hypoconstrictive variants). Maximum normotensive effect of the therapy and maximal efficacy in treating vertigo and headaches is reached in combinational therapy with vinpocetin and complex magnesium medication. a combination of complex magnesium medication with bylobil potentiates antiasthenic effect, mostly through diminishing excessive neuron muscular irritability and paresthesiae.Key words: teenagers, magnesium, b6 vitamin, cavinton, bylobil, potentiative therapy, early forms of cerebrovascular diseases

POSSIBILITIES OF COMBINATIONAL MAGNESIAL AND NEUROPROTECTOR THERAPY IN PATIENTS WITH EARLY CEREBROVASCULAR PATHOLOGY

The serum level of magnesium was evaluated in 232 teenagers and adolescents with early cerebrovascular diseases aged 16–21 years. In cases of magnesium deficiency, monotherapy with complex magnesium medication is an effective treatment both for concurrent magnesium deficiency and for early forms of cerebrovascular pathology with different patterns of vascular response (hyper_ and hypoconstrictive variants). Maximum normotensive effect of the therapy and maximal efficacy in treating vertigo and headaches is reached in combinational therapy with vinpocetin and complex magnesium medication. a combination of complex magnesium medication with bylobil potentiates antiasthenic effect, mostly through diminishing excessive neuron muscular irritability and paresthesiae.Key words: teenagers, magnesium, b6 vitamin, cavinton, bylobil, potentiative therapy, early forms of cerebrovascular diseases