Eight years after Robert Nussbaum and colleagues showed that mutations in α-synuclein were sufficient to cause Parkinson disease (Polymeropoulos et al., 1997), a clear biological function for this presynaptic protein has yet to be found. One thing that does seem certain is that α-synuclein toxicity is related to dose, because extra copies of the gene can also lead to neurodegeneration (see ARF related news story). In yesterday's Cell, Thomas Sudhof and colleagues report that, in some cases at least, overexpression of transgenic α-synuclein can have a protective role. It turns out the protein prevents neurodegeneration brought on by deletion of another protein called cysteine-string-protein-α (CSPα) in mice. In addition, the researchers report that ablation of endogenous α-synuclein exacerbates the degeneration caused by CSPα loss. The findings offer new clues to a chaperone role of α-synuclein and also suggest that the line between too much and too little of the protein is rather fuzzy.
First author Sreeganga Chandra and colleagues uncovered the α-synuclein/CSPα connection when they crossed transgenic mice expressing human or mouse α-synuclein with CSPα knockout mice. These knockouts usually die within the first month after birth, but offspring of the crosses, expressing typically fivefold more synuclein than normal, lived to at least 16 months (the maximum tested so far). The rescue was not limited to lifespan. CSPα-negative mice have a host of problems, including neurodegeneration, gliosis, synapse malfunction, deterioration of the neuromuscular junction, and motor impairment. Overexpression of α-synuclein rescued all of these problems. The A30P α-synuclein mutant that causes Parkinson disease (PD) in humans, however, failed to protect against CSPα loss.
The authors write that "rescue of a lethal mouse mutant by a nonrelated transgene is highly unusual, if not unique," and they acknowledge the possibility that α-synuclein might act in some fortuitous, indirect manner. However, there are indications that this is not so. The authors noticed that photoreceptors in the transgenic crosses neither express α-synuclein nor are rescued from neurodegeneration, indicating that synuclein acts in a cell-autonomous fashion. So what is synuclein doing to protect neurons from the ravages of CSPα loss?
To answer this, the authors looked to the biological function of CSPα. Together with Hsc70 and SGT, CSPα forms a chaperone complex involved in the folding and refolding of SNARE complexes that are crucial for the synthesis and recycling of synaptic vesicles. CSPα can also activate the ATPase activity of Hsc70 directly. But the authors failed to find any evidence that α-synuclein can act as a substitute in either regard.
If it is not taking over for CSPα, maybe it is affecting some downstream process, the scientists reasoned. With this in mind, they looked to see if CSPα loss affected levels of its partners or substrates. Sure enough, they found that levels of Hsc70, Hsp70, and the SNARE protein SNAP-25 were reduced in brains or cultured cortical neurons from CSPα knockouts. They also found that adding transgenic α-synuclein restored levels of Hsc70 and Hsp70, but could not restore levels of SNAP-25. However, when the authors immunoprecipitated SNARE complexes using antibodies to SNARE proteins synaptobrevin or syntaxin, they found that α-synuclein could restore SNARE SNAP-25 that was missing in the knockout animals. The results indicate that even though α-synuclein cannot restore total levels of SNAP-25, it promotes its recruitment into SNARE complexes, effectively ensuring that these do not become SNAP-25 deficient. The findings are in keeping with previous reports that α-synuclein plays a role in the synapses (see ARF related news story and ARF news story).
"These studies highlight a dual role for α-synuclein in neurodegeneration: Mutant α-synuclein or the abnormal accumulation of wild-type α-synuclein induces neurodegeneration, whereas the normal function of α-synuclein helps to enhance synaptic activity in integrity," write Nancy Bonini and Benoit Giasson, University of Pennsylvania, Philadelphia, in an accompanying Cell Preview.
While these studies provide a snapshot of at least some of α-synuclein's activities, there are still many unanswered questions. For example, how are the toxic and neuroprotective roles of α-synuclein related, if at all, and what role might CSPα play in Parkinson disease? Bonini and Giasson also raise the possibility that upregulation of CSPα might hold therapeutic promise for treating neurodegenerative disease. At least we now have the first compelling evidence for the physiological activity of normal α-synuclein in vivo, according to these two commentators.—Tom Fagan
- Synuclein and Parkinson's—It's All in the Dose
- α-Synuclein Appears to Regulate Synaptic Vesicles
- More Evidence Fusing Synuclein with Vesicles
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- Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell. 2005 Nov 4;123(3):383-96. PubMed.
- Bonini NM, Giasson BI. Snaring the function of alpha-synuclein. Cell. 2005 Nov 4;123(3):359-61. PubMed.