An alternatively spliced form of rodent alpha-synuclein forms intracellular inclusions in vitro: role of the carboxy-terminus in alpha-synuclein aggregation.
In the rat, the -synuclein gene is alternatively spliced and exists in three forms, rat synuclein 1 (rSYN1), synuclein 2 (rSYN2) and synuclein 3. rSYN2 cDNA encodes a 149 amino acid protein that is homologous to rSYN1 and human -synuclein for the first 100 amino acids, but is divergent for the 49 amino acid carboxy-terminal region. We demonstrate here that rSYN2 forms small aggregates throughout the cytoplasm when overexpressed in human H4 cells, whereas rSYN1 expression is diffuse. Inhibition of the proteasome promotes the formation of larger, cytoplasmic rSYN2 inclusions in transfected cells. Although a survey of the available databases suggests that there is no human splice form equivalent of rSYN2, thus arguing against a direct role in Lewy body formation and Parkinson's disease, these data nonetheless suggest that modifications of the carboxy-terminal region of -synuclein predispose it to inclusion formation.
McLean
Pamela J
PJ
Alzheimer's Disease Research Unit, Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital East, 114 16th Street, Charlestown, MA 02129, USA.
Hyman
Bradley T
BT
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D005091:Exons / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007438:Introns / Q000235:genetics; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D051843:Synucleins; D014162:Transfection; D014407:Tumor Cells, Cultured; D051844:alpha-Synuclein
D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein