Autopsy of a 78-year-old patient with Parkinson's disease shows brainstem and cortical Lewy bodies. The major component of Lewy bodies is alpha-synuclein. Which post-translational modification of alpha-synuclein is most critical for its aggregation into pathological amyloid fibrils?
- A Ubiquitination at Lysine 6 — marks alpha-synuclein for proteasomal degradation in normal neurons
- B Nitration at Tyrosine 39 — the dominant modification in MPTP-induced parkinsonism models
- C Phosphorylation at Serine 129 (pSer129) — over 90% of Lewy body alpha-synuclein is phosphorylated at this residue, strongly correlating with fibril formation and toxicity ✓
- D SUMOylation at Lysine 96/102 — inhibits fibril formation and is protective against aggregation
Explanation
Phosphorylation of alpha-synuclein at Serine 129 (pSer129) is the most abundant post-translational modification found in Lewy bodies — >90% of aggregated alpha-synuclein in PD brains is pSer129-positive, compared to <4% in normal brain. This modification is mediated by casein kinase-2 (CK2), PLK2, and LRRK2-regulated kinases, and promotes alpha-synuclein oligomerisation and fibril formation by altering its C-terminal electrostatic interactions and chaperone binding. pSer129 is the standard IHC marker for synucleinopathy pathology (used alongside ubiquitin and p62). Ubiquitination is a secondary modification; Tyr39 nitration occurs but is not the dominant modification; SUMOylation is generally protective.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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