Causes of Parkinson's disease: genetics of DJ-1.
ABSTRACT The identification of Mendelian mutations in rare forms of familial Parkinson's disease (PD) have provided significant insights into the molecular pathogenesis of this common complex disorder. DJ-1 is the third of four genes known to be definitively causal in familial PD, the three others being alpha-synuclein, parkin and the recently identified PINK1. Mutations in the DJ-1 gene were identified in two European families, a Dutch kindred harbouring a large homozygous genomic deletion encompassing exons 1-5 of the gene and an Italian kindred with a homozygous L166P missense mutation. The clinical phenotype of the two families was similar to that of parkin cases. Age of onset was in the mid-thirties with good responsiveness to l-dopa and slow disease progression. Focal dystonias and blepharospasm were also evident as were behavioural disturbances early in the course of the disease. To date, there are no studies of pathological material from known DJ-1 patients. It therefore remains to be determined whether these patients form Lewy bodies and/or Lewy neurites, the eosinophilic fibrillary inclusions that contain predominantly alpha-synuclein and that are the pathological hallmark of PD.
SourceAvailable from: Cristine Alves da Costa[Show abstract] [Hide abstract]
ABSTRACT: Parkinson's disease (PD) is a movement disorder of high prevalence in the elderly. It is characte-rized by a loss of dopaminergic neurons and the presence of intracytoplasmic inclusions named Lewy bodies. To date six familial PD-associated proteins have been identified so far. Some of them are implicated in the de-velopment of either autosomal dominant (-synuclein and LRRK2 (leucine-rich repeat kinase 2/dardarin) or early-onset recessive (parkin, DJ-1, PINK1 (PTEN-induced kinase-1) and ATP13A2) PD forms. A number of genetic studies have shown that 50% of the recessive forms are linked to mutations on parkin gene, followed by PINK1 (8-15%) and DJ-1 (1%). The purpose of this review is to provide an overview of the emerging data on the cellular and molecular biology of DJ-1. DJ-1 is a ubiquitous protein that was first described as an onco-gene. Nevertheless, after its association to monogenic PD a number considerable data aiming at understand-ing its implication in the physiopathology of PD was produced. This review will describe the main advances concerning the function of DJ-1. A considerable progress that was only possible due to a better understanding of DJ-1 structure, genetics, distribution and development of in vivo models. All these points along with the des-cription of recent data showing the interaction of DJ-1 with other PD-associated proteins will be given.Current Molecular Medicine 11/2007; 7(7):650-657. DOI:10.2174/156652407782564426 · 3.61 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Glutamate plays a complex role in many aspects of Parkinson's disease including the loss of dopaminergic neurons, the classical motor symptoms as well as associated non-motor symptoms and the treatment-related side effect, L-DOPA-induced dyskinesia. This widespread involvement opens up possibilities for glutamate-based therapies to provide a more rounded approach to treatment than is afforded by current dopamine replacement therapies. Beneficial effects of blocking postsynaptic glutamate transmission have already been noted in a range of preclinical studies using antagonists of NMDA receptors or negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), while positive allosteric modulators of mGlu4 in particular, although at an earlier stage of investigation, also look promising. This review addresses each of the key features of Parkinson's disease in turn, summarising the contribution glutamate makes to that feature and presenting an up-to-date account of the potential for drugs acting at ionotropic or metabotropic glutamate receptors to provide relief. Whilst only a handful of these have progressed to clinical trials to date, notably NMDA and NR2B antagonists against motor symptoms and L-DOPA-induced dyskinesia, with mGlu5 negative allosteric modulators also against L-DOPA-induced dyskinesia, the mainly positive outcomes of these trials, coupled with supportive preclinical data for other strategies in animal models of Parkinson's disease and L-DOPA-induced dyskinesia, raise cautious optimism that a glutamate-based therapeutic approach will have significant impact on the treatment of Parkinson's disease.Journal of Neural Transmission 02/2014; 121(8). DOI:10.1007/s00702-014-1176-4 · 2.87 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: A large number of mutations and polymorphisms associated with neurodegenerative disorders have been described during the last years. These findings have been helpful to improve our knowledge about the pathogenesis of these disorders. In this review we describe the genetic alterations and variants that cause or predispose to develop several neurodegenerative disorders, such as Huntington’s disease, Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease and other parkinsonisms. We also comment on the possible pathogenic mechanism of these mutations, clinical features and the usefulness of this information for the diagnosis and management of these disorders.Medicina Clínica 05/2006; 126(17):662-670. DOI:10.1157/13087844 · 1.25 Impact Factor