Understanding Südhof

If you are tired of reading articles telling the same story, repeating or confirming established standpoints, then you need to read the recent article by the team of Südhof (2005) published in the journal Cell. The article deals with two proteins: α-synuclein, and cystein-string protein-α (CSP-α). The results shows a curious phenomenon in which one protein can rescue the deficits caused by the absence of the other.
α-synuclein is a synaptic protein that appears mutated in some hereditary forms of Parkinson disease. Although the biochemical mechanism is unknown, it has been found that α-synuclein forms proteinaceous inclusion (Lewis bodies) similar to those found in Alzheimer's disease. Recently, it was reported that α-synuclein disperses from the terminal in response to neural activity. Deleting α-synuclein from the genome apparently has no consequences (Chandra et al., 2004). Only when both α- and β-synuclein are deleted, dopamine levels decreased by 20%. So, it seems that α-synuclein is not essential for neural function.
The cystein-string protein-α is a chaperone associated with the synaptic vesicle presumably via the fatty acids attached to cysteins residues of the cystein domains (Gundersen et al., 1994). CSP-α has a DNA-J domain that mediate interactions with the heat-shock protein and cognates (Hsp70/Hsc70) chaperone ATPases. It is able to both co-assemble with Hsc70 and turn on its ATPase activity.
Südhof points out that the synaptic terminal may be very active and has a large turnover of proteins. Some of these proteins may have defects and need to be re-folded or recycled. Since the synaptic terminal is far away from the soma it may require a private repairing machinery to ensure that misfolded and defected proteins are removed. He says:

"The synaptic vesicle localization and cochaperone activity of CSPα suggest that it may function in preventing the accumulation of nonnative, potentially toxic molecules during the continuous operation of a nerve terminal."

Südhof and co-workers used overexpression of both wild type and mutant of α-synuclein to rescue the phenotype caused by the absence of CSP-α. They noticed that the CSP-α mice have levels of α-synuclein reduced by 20%. But the reduction of α-synuclein per se does not seem to be a problem, as its deletion causes no severe deficits. Interestingly, the overexpression of human, but not murine α-synuclein rescues the phenotype. In addition, the α-synuclein mutant A30T does not rescue the phenotype. This mutant cannot anchor to the membrane, suggesting that the α-synuclein must be attached to prevent neurodegeneration.
α-synuclein, then, must have another yet to be discovered function beside clogging the protein-recycling machinery of the cell.