α-Synuclein

2022-05-31: reference:

α-Synuclein (SNCA) #

• Protein for synaptic vesicle transport. Fibrils of α-synuclein are the primary structural component of the lewy bodies (which are found in cortex and Substantia Nigra) of Parkinson’s.
• Lewy bodies in are formed by acceleration of α-syn aggregation of failure of clearance, whether by ROS and decline in antioxidants like DJ-1, Amyloid β, Tau, failure of ubiquitin, failure of lysosomal-mediated autophagy.
• A role for α-synuclein in the regulation of dopamine biosynthesis.
  • Colocalization with α-synuclein identified the Mitochondria as a site of Tyrosine Hydroxylase expression, in complex with PP2A, AADC. GTPCH, VMAT, and DJ-1.
• Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease (lots of cool figures)
  • Inhibits SNARE complexes and destabilizes microtubules.
  • Along with its aggregation, mitochondrial dysfunction and intracellular iron accumulation converge to cause the Parkinson’s pathogenesis.
    • Interaction of neuromelanin and iron in substantia nigra and other areas of human brain
      • Only the substantia nigra, and to a lesser extent the locus coeruleus, had a free radical signal consistent with that of neuromelanin… the structure of the pigment may differ in these two regions…
  • One nail in the coffin for the destruction of these neurons is α-synuclein aggregates blocking vesicular docking at DAT, preventing dopamine recycling, and prevents viscular docking of dopamine by interfering with - blocking - SNARE assembly.
  • Prevents the fusion of lysosomes with autophagosomes, whereby Ferritin is broken down in the acidic Autophagosome and iron is unable to be retrieved and thus causes Lipid Peroxidation, escaping the membrane along with Hydrogen Peroxide.
    • The autophagosomes then accumulate. For some reason calcium concentrations increase and PP2B is activated to mediate… inauspicious processes.
      • PP2B activity is not sufficient to promote TFEB translocation and has not been a successful therapeutic target in Parkinson’s (calcium concentrations are elevated)
  • One example of non-transferrin-bound iron entry is VGCCs on dopaminergic neurons.
  • PCBP1 participates in iron delivery to iron sulfur clusters for proteins such as IRP1 and to enzyme active sites. PCBP2 chaperones iron towards Ferroportin. PCBP1-4 (all of them) can deliver iron to ferritin.
  • [Amphipathic lipid packing sensor]
• Differentially expressed in brain regions at the Mitochondria whereby it can inhibit complex I of the Electron Transport Chain.