Further SNCA point mutations

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Rejko Krüger, Olaf Riess and colleagues (A30P, 1998); J. J. Zarranz, J. G. de Yebenes and colleagues (Cruces Hospital, Baracaldo, and University of the Basque Country; E46K, 2004); Silke Appel-Cresswell, Matthew Farrer and colleagues (University of British Columbia, Vancouver), and, separately, Christos Proukakis, A. H. Schapira and colleagues (University College London) (H50Q, both 2013); Suzanne Lesage, A. Brice and colleagues (Paris, French family) and A. P. Kiely, J. L. Holton and colleagues (Queen Square Brain Bank, London, British family) (G51D, both 2013). Funders were not read.

What happened

After A53T (landmark 4), families revealed more "missense" mutations (one amino-acid swapped in the protein). A30P appeared in Nature Genetics 18:106–108 (1998) in a paper titled "Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease"; only the title and authors could be read. E46K was found in a Spanish family with autosomal dominant parkinsonism, dementia and visual hallucinations; autopsy showed numerous Lewy bodies in cortical and subcortical areas and no Alzheimer pathology (Ann Neurol 55:164–173, 2004). H50Q was reported twice in 2013: in a patient with dopa-responsive Parkinson's and a family history of parkinsonism and dementia, with protein modelling suggesting it disturbs the same amphipathic (fat-binding) alpha helix as the earlier mutations (Mov Disord 28:811–813), and in a pathologically proven case (Neurology 80:1062–1064). G51D was reported in two families. A French family had a parkinsonian-pyramidal syndrome: early onset, moderate levodopa response, rapid progression and marked pyramidal signs, found by exome sequencing of three patients (Ann Neurol 73:459–471, 2013). A British family had young-onset, levodopa-responsive parkinsonism; the proband's brain showed widespread neuronal alpha-synuclein inclusions and oligodendroglial inclusions like the glial cytoplasmic inclusions of multiple system atrophy (Acta Neuropathol 125:753–769, 2013). A later comparison of three G51D cases with one H50Q case and one SNCA duplication case found G51D disease distinct: parkinsonism with dementia, hallucinations, autonomic failure and pyramidal signs, with Parkinson-plus-MSA pathology, while the H50Q case looked like late-onset idiopathic Parkinson's with good levodopa response (Mol Neurodegener 10:41, 2015).

Why it moved us toward a cure

Several mutations sit in one stretch of the protein, the same amphipathic helix, per the H50Q authors' modelling, so that region matters for toxicity. Test-tube work shows the two newest differ: H50Q speeds aggregation while G51D slows it (Rutherford 2014). Different mutations give different diseases, hinting that distinct clump shapes ("strains") drive distinct disorders, which matters for designing drugs and tests (landmark 27). In M83 transgenic mice, G51D patient brain extract produced no overt illness for up to 18 months, only a subclinical synuclein pathology that resembled Parkinson's aggregates more than MSA ones (Lau 2023).

Outcome

Advanced. These mutations are rare, and no therapy specific to them exists.

Sources

• Krüger et al., Nat Genet 1998;18:106–108
• Zarranz et al., Ann Neurol 2004;55:164–173, DOI 10.1002/ana.10795, PMID 14755719
• Appel-Cresswell et al., Mov Disord 2013;28:811–813, DOI 10.1002/mds.25421, PMID 23457019 · Proukakis et al., Neurology 2013;80:1062–1064, DOI 10.1212/WNL.0b013e31828727ba, PMID 23427326
• Kiely et al., Acta Neuropathol 2013;125:753–769 · Kiely et al., Mol Neurodegener 2015;10:41
• Lesage et al., G51D, Ann Neurol 2013;73:459–471, DOI 10.1002/ana.23894, PMID 23526723 · Rutherford et al., J Neurochem 2014;131:859–867, DOI 10.1111/jnc.12806 · Lau et al., Acta Neuropathol Commun 2023;11:72
• Not yet verified: A30P's family and findings (the PubMed record has no abstract); Lesage's family size beyond the three patients sequenced; the Proukakis paper's detail beyond its one-line abstract; funders of all papers; the A30P link to lipid binding (not read).