It describes the discovery of the genetic defect associated with a rare, inherited form of Parkinson’s disease. Our team had previously localized the genetic defect to a small region of chromosome 1 in two European families with an early-onset form of the disease. Fine mapping analysis and a positional cloning strategy led us to the identification of mutations in a gene called DJ-1 in both families. The DJ-1 gene has been conserved during evolution and is highly expressed in the brain and body tissues. Yet its function remains basically unknown, and nobody had previously linked this gene to brain function or disease. The discovery that DJ-1 is mutated into a form of human neurodegeneration is therefore even more interesting because so little is known about the biology and pathology of this gene. The novel link established here between DJ-1 and neurodegeneration brings therefore the potential of unraveling the role of novel pathways in the pathogenesis of Parkinson’s disease, leading to new ideas about therapeutic strategies.

Parkinson’s disease is a frequent and devastating neurological disease of mostly unknown causes. Its prevalence will increase in the future due to the ageing of the population, and, currently, there are no effective therapies for stopping or preventing this disease. The characteristic signs (tremor at rest, muscular rigidity, and slowness of movements) appear because of the severe degeneration and premature death of a specific population of neurons in the brain, that produce a substance called dopamine. The available therapies are effective in controlling the symptoms for many years, but they are unable to stop or slow down the disease progression, mainly because of the scarcity of knowledge about causes and mechanisms of the neuronal degeneration. Understanding the mechanisms of the disease at a molecular level better is therefore the way to develop a cure. In most cases, Parkinson’s disease appears in an individual after the age of 60, and it is a sporadic disease (in other words, there are no other affected family members). In these common, late-onset forms, the causes of the disease remain unknown. In rare cases, especially those with a very early onset (before age of 40), Parkinson’s disease might be inherited, meaning that a major genetic defect might be at the roots of the disease in these forms. For the researchers interested in finding the causes and mechanisms of Parkinson’s disease, these rare forms are something like simplified natural models, which might be extremely useful in disentangling the complexity of the common, non-hereditary forms of this disease. Defects in only two genes had been firmly implicated in rare hereditary forms of Parkinson’s disease in the past few years: these genes are called alpha-synuclein and parkin. Our work led to the identification of a third gene, DJ-1, bearing defects in rare cases of early-onset Parkinson’s disease. It is now an urgent priority to study the normal function of this gene in the cell, in order to understand how the defect in this gene causes the death of the dopamine-producing neurons. Importantly, in most cases of Parkinson’s disease these genes are not defective, but the molecular networks unraveled by these genes might be disrupted due to different and unknown causes.

After obtaining my M.D. and a specialization in clinical neurology at the University of Roma "La Sapienza," I worked there for several years in the Parkinson’s disease center. Since the early 1990s I became interested in studying the causes of this disease, and, together with my Roman colleagues Edito Fabrizio, Nicola Vanacore, and Giuseppe Meco, I decided to focus on the familial forms of Parkinson’s disease, an area of rather limited interest for the researchers at that time. Early in 2000, after a few years of clinical research, I moved to the Erasmus University Rotterdam (The Netherlands), joining the group run by Peter Heutink and Ben Oostra, who were leading a research team with strong interests in the molecular genetics of neurodegenerative diseases. In Rotterdam, I studied molecular genetics and then became personally involved in the laboratory research aimed at the identification of the genes involved in Parkinson’s disease.