Although we have known about Parkinson's disease for almost 200 years (it was discovered by the English physician James Parkinson in 1817), the role of genetics in the pathology of the disease has only recently emerged.
   Recently, two new genes associated with Parkinson's disease have been reported. The first, called alpha-synuclein, is mutated in an autosomal-dominant type of Parkinson's disease. The second, uncovered in April 1998, codes for a protein called parkin, which is associated with a juvenile autosomal-recessive form of Parkinson's disease (AR-JP).
   One of the pathological features of most types of Parkinson's disease is the appearance of an inclusion body, known as a Lewy body, in many regions of the brain. The Lewy body is associated with neuronal degeneration, and is also seen in Alzheimer's disease. It may be no coincidence that alpha-synuclein is found in Lewy bodies. In AR-JP, however, there is no Lewy body formation. In spite of these apparent differences between these two types of Parkinson's disease, there are some tantalizing links at the molecular level.
   The best ways to visualize Lewy bodies in brain tissue is to use antibodies against ubiquitin, because they contain high levels of ubiquitinated proteins. In cells, ubiquitin first binds to proteins displaying degradation signals, then recruits further ubiquitin molecules to form a poly-ubiquitin chain. This 'flags' the protein for destruction by the 26S proteasome. In neurodegenerative disease, incompletely degraded, ubiquitinated proteins accumulate in Lewy bodies. It is intriguing that alpha-synuclein, which is responsible for a subset of cases of Parkinson's disease, should be found in the same place.
   Enter parkin. After cloning and sequencing the suspected Parkinson's disease gene, the researchers compared their sequence to those in the database. They found that parkin contains an ubiquitin-like domain and a RING finger motif, implicated in interactions with DNA [and more recently, with other proteins]. Could parkin function in a similar way to ubiquitin proteins, and its defect in AR-JP interfere with the ubiquitin-mediated protein degradation pathway?
   While all roads [for the present] lead to a defect in ubiquitin-mediated pathways as a cause of Parkinson's and perhaps other neurodegenerative diseases, the two types of Parkinson's disease described here account for only a small fraction of the total number of Parkinson's disease cases. However, these early forays will prove extremely valuable for tracking down other genetic factors that could be involved in neurodegenerative disease.