Parkinson Disease: van der Brug M

Cookson MR, van der Brug M. · Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20982-3707, USA. · Exp Neurol. · Pubmed #17603039 links to  free full text

Abstract: Mutations in the SNCA gene are causal for familial Parkinson disease/Lewy body disease. alpha-Synuclein is a small acidic protein that binds loosely to the surface of vesicles and may play a role in synaptic dynamics, although its normal function remains somewhat unclear. What is clear is that point mutations or increased expression of wild type alpha-synuclein causes disease. A great deal of literature supports the overall hypothesis that alpha-synuclein is damaging to neurons because it is inherently prone to aggregation; mutations or increased concentration of the protein both increase this tendency. An unproven, but popular, contention is that the toxic species are small oligomers that are relatively soluble, which may react with membranes to damage key processes within the cell. The details of this process, especially in determining the order of events and the requirement of particular processes in cell death, are unclear. Derangements in vesicle processing, including synaptic function, protein turnover, mitochondrial function and oxidative stress, have all been suggested to occur. Whether there is a sequence of events or whether these are interacting effects is unclear, but the outcome is to trigger cell death, by both apoptotic and non-apoptotic mechanisms depending on the system studied. In this article, we develop a framework for thinking about alpha-synuclein in terms of initiating events and secondary processes that are required to trigger neuronal dysfunction and cell death.

Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB. · Unitat de Genètica Molecular, Departament de Genòmica i Proteòmica, Institut de Biomedicina de València-CSIC, E46010 València, Spain. · Neuron. · Pubmed #15541308 No free full text.

Abstract: Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.