On the Pathogenesis and Neuroprotective Treatment of Parkinson Disease: What have we Learned from the Genetic Forms of this Disease?

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of alpha-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, alpha-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of alpha-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.

l-DOPA-induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements?

“…Even so, the role played by neuroinflammation in PD is under intense debate (Gao et al, ; Marchetti & Abbracchio, ; McGeer & McGeer, ; Mena, Rodriguez‐Navarro, Ros, & de Yebenes, ; Niranjan, ; Tansey & Goldberg, ; Whitton, ). Accordingly, particular immunological responses in PD could be either detrimental or beneficial, with neurotoxic and neuroprotective mechanisms interacting in a delicate balance.…”

NP7 protects from cell death induced by oxidative stress in neuronal and glial midbrain cultures from parkin null mice

“…The special sensitivity of aged PK‐KO glia to oxidative stress while there is strong resistance in young PK‐KO cells, suggest that these cells are exposed to a greater oxidative challenge and that a compensatory GSH synthesis is increased for some time until it collapses with senescence and renders the cells more susceptible [16]. Furthermore, in the differential oxidative stress response between WT and PK‐KO cultures, parkin as an E3 ligase, which participates in the ubiquitin–proteasome system, protein aggregation and protein posttranslational modifications, may play a very important role [40–43].…”

Single Nucleotide Polymorphisms of PARKIN Gene in Ten Indian Populations

“…PARKIN gene mutations are the most frequent cause of autosomal recessive Parkinson's disease in the populations from all over the world. Till date a wide variety of mutations in the PARKIN gene have been detected, including exon deletions and duplications, as well as point mutation (Klein et al 2005;Madegowda et al 2005;Biswas et al 2006;Abbas et al 1999;Chaudhary et al 2006;Mena et al 2008). A most recent study has identified a deletion hot spot between exons 2 and 5.…”