Novel PINK1 mutations in early-onset Parkinsonism

ArticleinAnnals of Neurology 56(3):424-7 · September 2004with10 Reads
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.
    • "Subsequent studies, focusing on complex I-mediated reactive oxygen species formation link PD to a vicious circle of oxidative stress and bioenergetic failure . Moreover, there is compelling evidence that mitochondrial quality control and stress responses are affected by PD-associated genes (Hatano et al., 2004; Mills et al., 2008; Mullin and Schapira, 2013). At the cellular genetic level, reports have indicated that mitochondrial DNA (mtDNA) deletion formation may contribute to etiology (Reeve et al., 2013); however, these isolated findings cannot fully explain the gross neuronal loss seen in PD. "
    [Show abstract] [Hide abstract] ABSTRACT: Like any organ, the brain is susceptible to the march of time and a reduction in mitochondrial biogenesis is a hallmark of the ageing process. In the largest investigation of mitochondrial copy-number in Parkinson’s disease to date and by utilizing multiple tissues, we demonstrate that reduced mtDNA copy-number is a biomarker for the aetiology of PD. We used established methods of mtDNA quantification to assess the copy-number of mtDNA in n=363 peripheral blood samples, n=151 substantia nigra pars compacta (SNpc) tissue samples and n=120 frontal cortex tissue samples from community based PD cases fulfilling UK-PD Society brain bank criteria for the diagnosis of PD. Accepting technical limitations, our data show that PD patients suffer a significant reduction in mtDNA copy-number in both peripheral blood and the vulnerable substantia nigra pars compacta when compared to matched controls.
    Full-text · Article · Nov 2015
    • "In the current PD genetics nomenclature, 18 specific chromosomal regions are termed PARK, and 18 PD-related genetic loci (PARK1-18) were identified in chronological order [27]. Mutations described for these familial forms of PD, include autosomal dominant mutations of SNCA (PARK1, PARK4) [28], UCHL1 (PARK5), LRRK2 (PARK8) [29], HTRA2 (PARK13) [30] or autosomal recessive mutations of Parkin (PARK2) [31], PINK1 (PARK6) [32], DJ-1 (PARK7) [33] and ATP13A2 (PARK9) [34]. A list of the PARK PD-related genes is provided inTable 1. PARK genes are associated with PD. "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) with motor and nonmotor symptoms. Defective mitochondrial function and increased oxidative stress (OS) have been demonstrated as having an important role in PD pathogenesis, although the underlying mechanism is not clear. The etiopathogenesis of sporadic PD is complex with variable contributions of environmental factors and genetic susceptibility. Both these factors influence various mitochondrial aspects, including their life cycle, bioenergetic capacity, quality control, dynamic changes of morphology and connectivity (fusion, fission), subcellular distribution (transport), and the regulation of cell death pathways. Mitochondrial dysfunction has mainly been reported in various non-dopaminergic cells and tissue samples from human patients as well as transgenic mouse and fruit fly models of PD. Thus, the mitochondria represent a highly promising target for the development of PD biomarkers. However, the limited amount of dopaminergic neurons prevented investigation of their detailed study. For the first time, we established human telomerase reverse transcriptase (hTERT)-immortalized wild type, idiopathic and Parkin deficient mesenchymal stromal cells (MSCs) isolated from the adipose tissues of PD patients, which could be used as a good cellular model to evaluate mitochondrial dysfunction for the better understanding of PD pathology and for the development of early diagnostic markers and effective therapy targets of PD. In this review, we examine evidence for the roles of mitochondrial dysfunction and increased OS in the neuronal loss that leads to PD and discuss how this knowledge further improve the treatment for patients with PD.
    Full-text · Article · Jun 2015
    • "Recessively inherited, early-onset or X-linked atypical parkinsonism PARK2 (Parkin) Numerous exon deletions, duplications and missense mutations 600116 [109] PINK1 Rare locus and exon deletions. Numerous missense mutations, including E129X, Q129fsX157, P196L, G309N W437X, G440E, Q456X 605909 [147,151] DJ-1 Deletions and missense: dup168-185, A39S, E64D, D149A, Q163L, L166P, M261I. 606324 [123] DNAJC6 Splice site c.801 -2 A > G and truncating mutation Q734X 615528 [70] ATP13A2 Missense: L552fsX788, M810R, G877R, G1019fsX1021. "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. Although best described as a movement disorder, the condition has prominent autonomic, cognitive, psychiatric, sensory and sleep components. Striatal dopaminergic innervation and nigral neurons are progressively lost, with associated Lewy pathology readily apparent on autopsy. Nevertheless, knowledge of the molecular events leading to this pathophysiology is limited. Current therapies offer symptomatic benefit but they fail to slow progression and patients continue to deteriorate. Recent discoveries in sporadic, Mendelian and more complex forms of parkinsonism provide novel insight into disease etiology; 28 genes, including those encoding alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2) and microtubule-associated protein tau (MAPT), have been linked and/or associated with PD. A consensus regarding the affected biological pathways and molecular processes has also started to emerge. In early-onset and more a typical PD, deficits in mitophagy pathways and lysosomal function appear to be prominent. By contrast, in more typical late-onset PD, chronic, albeit subtle, dysfunction in synaptic transmission, early endosomal trafficking and receptor recycling, as well as chaperone-mediated autophagy, provide a unifying synthesis of the molecular pathways involved. Disease-modification (neuroprotection) is no longer such an elusive goal given the unparalleled opportunity for diagnosis, translational neuroscience and therapeutic development provided by genetic discovery.
    Full-text · Article · Jun 2014
Show more