Novel PINK1 mutations in early-onset parkinsonism

Juntendo University, Edo, Tōkyō, Japan
Annals of Neurology (Impact Factor: 11.91). 09/2004; 56(3):424-7. DOI: 10.1002/ana.20251
Source: PubMed

ABSTRACT PINK1 was recently found to be associated with PARK6 as the causative gene. We performed mutation analysis in eight inbred families whose haplotypes link to the PARK6 region. We identified six pathogenic mutations (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated families. All sites of mutations were novel, suggesting that PINK1 may be the second most common causative gene next to parkin in parkinsonism with the recessive mode of inheritance.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by two major neuropathological hallmarks: the degeneration of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies in the surviving SN neurons, as well as other regions of the central and peripheral nervous system. Animal models have been invaluable tools for investigating the underlying mechanisms of the pathogenesis of PD and testing new potential symptomatic, neuroprotective and neurorestorative therapies. However, the usefulness of these models is dependent on how precisely they replicate the features of clinical PD with some studies now employing combined gene-environment models to replicate more of the affected pathways. The rotenone model of PD has become of great interest following the seminal paper by the Greenamyre group in 2000 (Betarbet et al., 2000). This paper reported for the first time that systemic rotenone was able to reproduce the two pathological hallmarks of PD as well as certain parkinsonian motor deficits. Since 2000, many research groups have actively used the rotenone model worldwide. This paper will review rotenone models, focusing upon their ability to reproduce the two pathological hallmarks of PD, motor deficits, extranigral pathology and non-motor symptoms. We will also summarize the recent advances in neuroprotective therapies, focusing on those that investigated non-motor symptoms and review rotenone models used in combination with PD genetic models to investigate gene-environment interactions.
    NeuroToxicology 12/2014; 46:101-116. DOI:10.1016/j.neuro.2014.12.002 · 3.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.
    Cellular and Molecular Life Sciences CMLS 11/2014; 72(4). DOI:10.1007/s00018-014-1774-1 · 5.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The last 2 decades represent a period of unparalleled advancement in the understanding of the pathogenesis of Parkinson disease (PD). The discovery of several forms of familial parkinsonism with mendelian inheritance has elucidated insights into the mechanisms underlying the degeneration of dopaminergic neurons of the substantia nigra that histologically characterize PD. α-Synuclein, the principal component of Lewy bodies, remains the presumed pathogen at the heart of the current model; however, concurrently, a diverse range of other mechanisms have been implicated. The creation of a coherent disease model will be crucial to the development of effective disease modifying therapies for sporadic PD. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurologic Clinics 11/2014; 33(1). DOI:10.1016/j.ncl.2014.09.010 · 1.61 Impact Factor