Unsumoylated α-synuclein aggregates into fibrils (right), whereas sumoylated α-synuclein doesn't (left).
Unsumoylated α-synuclein aggregates into fibrils (right), whereas sumoylated α-synuclein doesn't (left).
Sumoylation might prevent the protein aggregations that typify Parkinson's disease (PD), report.
Insoluble protein clusters are the hallmarks of several neurodegenerative diseases. In PD, neurons harbor clumps of the protein α-synuclein. What triggers these protein pileups remains obscure. A possible clue for PD came when researchers overexpressed α-synuclein in human kidney cells and found that the protein was modified by the addition of the small, ubiquitin-like molecule SUMO. Since sumoylation generally boosts the solubility of proteins, the result raised the possibility that SUMO proteins affect the aggregation of α-synuclein.
Krumova et al. tested whether sumoylating purified α-synuclein hindered it from clustering into fibrils, filaments similar to those detected in neurons of PD patients. If all of the α-synuclein molecules in a solution were sumoylated, no fibrils appeared. And even if only 10% of the molecules were sumoylated, fibril formation slowed dramatically.
SUMO molecules typically attach to two sites on α-synuclein, the researchers found. Compared with controls, cells that produced α-synuclein mutants lacking these two sites contained more protein clusters and were more likely to die by apoptosis. The scientists then genetically altered rats to manufacture the α-synuclein mutants specifically in neurons. Cell death surged in the substantia nigra, the brain region where large numbers of neurons perish in PD patients. But whether sumoylation goes awry in these patients remains unknown.
