{"entity":{"id":"alpha-synuclein","kind":"target","name":"Alpha-synuclein","aka":["a-synuclein","SNCA","alpha synuclein aggregates"],"tldr":"The protein that clumps inside brain cells in Parkinson's disease and related conditions. Nobody can yet see those clumps in a living person, which is why these diseases are still diagnosed by watching the patient.","summary":"Alpha-synuclein is a small presynaptic protein whose misfolded, aggregated forms define the synucleinopathies: Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Unlike amyloid and tau, which both have approved PET agents, no small molecule targeting misfolded alpha-synuclein has been approved by the FDA as a PET radiopharmaceutical, and the inability to quantify these aggregates in vivo limits accurate clinical diagnosis across the whole group.\n\nThe target is hard for physical reasons. The aggregates are intracellular and, in Parkinson's disease, present at far lower density than cortical amyloid plaques, and the protein has several conformational strains. The most advanced tracer, [18F]ACI-12589 from AC Immune, demonstrated this precisely in a 42-participant study published in Nature Communications in 2023: binding statistically separated multiple system atrophy patients from healthy controls and from other neurodegenerative disorders, with clear signal in cerebellar white matter and middle cerebellar peduncles, but showed limited binding in Parkinson's disease despite binding post-mortem Parkinson's tissue.\n\nThe competing measurement has already succeeded. Seed amplification assays on cerebrospinal fluid are reported at 87.7% sensitivity and 96.3% specificity for Parkinson's disease in the PPMI cohort, with a pooled meta-analysis across biomatrices at 0.86 and 0.92. What those assays cannot do is localise or quantify pathology, or measure whether a drug reduced it, and they are markedly less reliable in multiple system atrophy. That residual is where an imaging agent would have to earn its place.","asOf":"2026-09-23","links":[{"label":"[18F]ACI-12589 first-in-human, Nature Communications 2023","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10611796/"},{"label":"No approved small-molecule alpha-synuclein PET agent","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13121216/"},{"label":"Alpha-synuclein cannot currently be assessed accurately in vivo","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8466155/"},{"label":"Seed amplification assays: past, present and future roles","url":"https://www.movementdisorders.org/MDS/Scientific-Issues/posts/The-past-present-and-future-roles-of-a-synuclein-seed-amplification-assays.htm"},{"label":"Conference report: PET signal only in multiple system atrophy","url":"https://www.alzforum.org/news/conference-coverage/first-field-synuclein-pet-only-multiple-system-atrophy"}],"tags":["neurology","protein aggregate","unmet need"],"related":["tau-protein","amyloid-beta","opp-alpha-synuclein-pet-parkinsons","f-18"],"indications":["parkinsonian-syndromes"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"SNCA","hgnc":"HGNC:11138","ensembl":"ENSG00000145335","uniprot":"P37840","entrez":"6622","biology":"A 140-amino-acid presynaptic protein involved in vesicle trafficking, which misfolds into beta-sheet-rich oligomers and fibrils that accumulate as Lewy bodies in neurons or as glial cytoplasmic inclusions in multiple system atrophy. The aggregates are intracellular, conformationally heterogeneous and, in Parkinson's disease, present at low density.","whereFound":["Parkinson's disease: Lewy bodies and Lewy neurites in neurons","Dementia with Lewy bodies: cortical Lewy pathology","Multiple system atrophy: glial cytoplasmic inclusions, the one form a tracer has so far detected in vivo","Not a cancer target; the imaging rationale is neurological"],"targetClass":"other","prevalence":[]},"route":"/targets/alpha-synuclein/","neighbours":{"target":[{"id":"amyloid-beta","kind":"target","name":"Amyloid beta plaques","route":"/targets/amyloid-beta/"},{"id":"tau-protein","kind":"target","name":"Tau protein (neurofibrillary tangles)","route":"/targets/tau-protein/"}],"opportunity":[{"id":"opp-alpha-synuclein-pet-parkinsons","kind":"opportunity","name":"Alpha-synuclein PET: works for MSA, not for Parkinson's","route":"/opportunities/opp-alpha-synuclein-pet-parkinsons/"}],"isotope":[{"id":"f-18","kind":"isotope","name":"Fluorine-18","route":"/isotopes/f-18/"}],"indication":[{"id":"parkinsonian-syndromes","kind":"indication","name":"Parkinsonian syndromes","route":"/indications/parkinsonian-syndromes/"}]}}