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The enigma of alpha-synuclein
Commentary on "Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?"
Contributed by Dr. Gerald M. Stern, MD
London, United Kingdom
Since 1998, when synuclein (a-syn) was first identified in electric fish, there has been a tsunami of information concerning its relationship to neurodegenerative diseases (the present June 2013 edition of our Journal, includes four article with a-syn in the title and four referring to a-syn in the text). Yet, at least two aspects of this small 140 amino acid remain unresolved: the physiological role of a-syn and whether the aggregated form of the protein exercises a direct 'toxic' effect upon neurons causing cell death.
In health, a-syn is concentrated in pre-synaptic terminals of neuronal cell bodies and ganglia and is also expressed in astrocytes and oligodendrocytes. It is demonstrable in Schwann cells and in the peripheral nervous system. Its presence is not limited to the nervous system and is expressed in normal muscle, haematopoietic cells and the umbilical vein and artery and occurs in invertebrates as well as vertebrates. Thus while abundant in health, its physiological function remains largely unknown, although it has been shown that a-syn knockout mice appear to be normal.
From human clinical-pathological evidence, foetal dopaminergic cells, transplanted into parkinsonian brains, contain a-syn positive Lewy bodies and Lewy neurites 11-16 years after transplant surgery. Consistent with this, it has been shown experimentally that a-syn misfolds and aggregates into seeds formed within the host brain that transfer to the grafted neurons to induce a-syn aggregation; intracerebral injection of brain extracts containing aggregated a-syn into young a-syn transgenic mice, stimulates the formation of a-syn lesions in the host and later the mice show signs of motor dysfunction and premature death: the basis of the prion hypothesis.
The unresolved questions remain whether aggregated a-syn is a direct toxin causing neuronal death and if so what is the mechanism? Could the presence of altered a-syn reflect the process of cell death rather than the cause? Some have suggested that the presence of Lewy bodies and neurites containing a-syn within neurons, could mean that the formation of large cellular inclusions represent a protective process. Perhaps there are transient fashions in neuroscientific research? Is it too heretical to recall that it was not so long ago, that 'apoptosis' was the accepted mechanism of cell death and noteworthy that this explanation is rarely currently employed?