synphilin-1; sph1; alpha-synuclein-interacting protein (SNCAIP)

Function

• associates with alpha-synuclein
• ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A & leading to its subsequent proteasomal degradation
• in the absence of proteasomal degradation, ubiquitinated SNCAIP accumulates in cytoplasmic inclusion bodies
• homodimer (probable)
• heterodimer of isoform 1 & isoform 2 (probable)
• interacts with SIAH1, SIAH2, SNCA, RNF19A & PARK2
• isoform 2
  • inhibits the ubiquitin ligase activity of SIAH1 & inhibits proteasomal degradation of target proteins
  • inhibits autoubiquitination & proteasomal degradation of SIAH1, & thereby increases cellular levels of SIAH
  • modulates SNCA monoubiquitination by SIAH1
  • is subject to limited ubiquitination that does not lead to proteasomal degradation
  • has a strong tendency to form aggregates & can sequester isoform 1

Structure

• contains 6 ANK repeats

Compartment

• cytoplasm
• detected in cytoplasmic inclusion bodies, together with SNCA

Alternative splicing

named isoforms=6

Expression

• detected in brain (at protein level)
• widely expressed, with highest levels in brain, heart & placenta

Pathology

• defects in SNCAIP are a cause of Parkinson disease
• promotes formation of cytoplasmic inclusions
• detected in some Lewy bodies, but not Lewy neurites

Notes

• constructs encoding portions of SNCA & SNCAIP co-transfected in mammalian cells promote cytosolic inclusions resembling the Lewy bodies of Parkinson disease
• coexpression of SNCA, SNCAIP, & PARK2 result in the formation of Lewy body-like ubiquitin-positive cytosolic inclusions
• SNCAIP isoform 2 is particularly aggregatation-prone
• familial mutations in PARK2 disrupt the ubiquitination of SNCAIP & the formation of the ubiquitin-positive inclusions
• ubiquitination of Lewy body-associated proteins link PARK2 & SNCA in a common pathogenic mechanism through their interaction with SNCAIP

More general terms

• phosphoprotein
• ankyrin repeat domain protein (ANKRD)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=9627
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:9627
• OMIM: https://mirror.omim.org/entry/168600
• OMIM: https://mirror.omim.org/entry/603779
• UniProt: http://www.uniprot.org/uniprot/Q9Y6H5.html