SNCA (alpha-synuclein, P37840) - manual literature synthesis

No deep-research provider was available for this session. This file is a manual
synthesis written from the cached publications in publications/ and the UniProt
record (SNCA-uniprot.txt). Each claim carries its source.

Identity and structure

• 140-aa neuronal protein, the major component of Lewy bodies; originally cloned as
  NACP, the precursor of the non-Abeta component (NAC) of Alzheimer amyloid
  PMID:8248242.
• Intrinsically disordered in solution [PMID:8901511 "NACP exists as a mixture of rapidly equilibrating extended conformers and is representative of a class of \"natively unfolded\" proteins"].
• N-terminal imperfect KTKEGV repeats form an amphipathic helix on lipid surfaces; the
  acidic C-terminal tail stays unfolded PMID:11286556.
• Native oligomeric state is debated: Bartels et al. reported a helical tetramer
  PMID:21841800,
  whereas Fauvet et al. found predominantly disordered monomer in brain
  PMID:22315227.
  Burre et al. reconcile this partly: membrane binding drives multimerization
  PMID:25246573.

Physiological function at the presynapse

• Synaptic, raft-dependent localization PMID:15282274.
• SNARE chaperone: binds VAMP2 and promotes SNARE-complex assembly; synuclein triple
  knockouts show age-dependent decline PMID:20798282.
  The active form is the membrane-bound multimer PMID:25246573.
• Genetic cooperation with CSPalpha/DNAJC5 requires phospholipid binding
  PMID:16269331.
• Exocytosis: promotes fusion-pore dilation PMID:28288128;
  facilitates priming and fusion in PC12 cells PMID:30404828.
• Dopaminergic transmission: knockout mice show altered paired-pulse DA release
  PMID:10707987.
• Endocytosis: with PUFAs promotes clathrin-mediated endocytosis and SV recycling
  PMID:18980610.

Modulation of monoamine transporters and enzymes (peripheral, mostly overexpression)

• DAT inhibition PMID:12958153; SERT PMID:16882008; NET PMID:17156375.
• Tyrosine hydroxylase inhibition PMID:11943812.
• PLD inhibition is not reproduced PMID:19146388.
• GPX1 stimulation, single report PMID:23507046.

Metal and lipid binding

• High-affinity Cu(II) site at the N-terminus/His50 PMID:21319811; Cu(I) binding PMID:25495902.
• Ca2+ binding at the acidic C-terminus PMID:11312271.
• Fe and Mg modulate aggregation in vitro PMID:11850416.
• Not a fatty-acid carrier PMID:16687662.

Pathology

• Missense mutations and multiplications cause PARK1/PARK4 and DLB (UniProt DISEASE).
• Aggregates into amyloid fibrils, Lewy bodies and glial cytoplasmic inclusions;
  filament structures from MSA PMID:32461689.

Note on PMID:22219196

This PMID was supplied to the session as a key SNCA paper. The cached record is
"Glutathione s-transferase omega 1 activity is sufficient to suppress neurodegeneration
in a Drosophila model of Parkinson disease", a study of Drosophila GSTO1 and parkin;
alpha-synuclein is mentioned only in passing (4 mentions, background). It provides no
evidence about SNCA function.