UCSF

Neurodegenerative diseases are characterized by the accumulation and aggregation of particular proteins. In most cases, very little is known about the physiological function of these proteins; further, the manner in which their normal functions may contribute to the initiation of disease has not been well studied.

The protein alpha-synuclein has been implicated in both sporadic and familial forms of Parkinson's disease. Three point mutations in alpha-synuclein cause dominantly inherited forms of the disease, implying a causative role in the disorder. Although it localizes to nerve terminals, its role in neurotransmitter release remains poorly understood. Recently, it has been shown that modest increases in alpha-synuclein protein expression are sufficient to cause Parkinson's disease, suggesting that an increase in its normal function may initiate degeneration.

To understand the role of increased alpha-synuclein expression on nerve terminal physiology, we overexpressed alpha-synuclein in hippocampal neurons along with a fluorescent reporter of neurotransmitter release, VGLUT1-pHluorin. We find that increased expression of alpha-synuclein inhibits neurotransmitter release, and does so by reducing the size of the synaptic vesicle recycling pool. A mutation in alpha-synuclein linked to Parkinson's disease (A30P) that inhibits membrane binding abolishes this effect; however, the C-terminus is not required. Further, alpha-synuclein overexpression inhibits neurotransmitter release in hippocampal slices from transgenic mice. Importantly, we also show that increased alpha-synuclein expression inhibits neurotransmitter release in midbrain dopamine neurons. Biochemical experiments suggest that the decrease in recycling pool size may be due to a selective decrease in complexin and synapsin proteins. We also present preliminary evidence indicating a role for alpha-synuclein in the control of mitochondrial morphology. Overexpression of alpha-synuclein causes mitochondrial fragmentation, while the A30P mutant has a diminished ability to fragment mitochondria.

These experiments clarify the function of alpha-synuclein at the nerve terminal, and suggest a role for increased expression of the protein and altered synaptic activity in the initiation of Parkinson's disease pathogenesis. Further, we provide evidence for a previously unappreciated link between alpha-synuclein and mitochondria, an organelle whose dysfunction is central to the degeneration of neurons in Parkinson's disease.