Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism
Sapienza University of Rome, Roma, Latium, Italy Annals of Neurology
(Impact Factor: 9.98).
10/2004; 56(3):427-31. DOI: 10.1002/ana.20247
Two homozygous mutations in the PINK1 gene, encoding a mitochondrial putative protein kinase, recently have been identified in families with PARK6-linked, autosomal recessive early-onset parkinsonism (AREP). Here, we describe a novel homozygous mutation (1573_1574 insTTAG) identified in an AREP patient, which causes a frameshift and truncation at the C-terminus of the PINK1 protein, outside the kinase catalytic domain. The clinical phenotype includes early-onset (28 years) parkinsonism, foot dystonia at onset, good levodopa response, slow progression, early levodopa-induced dyskinesias, and sleep benefit, thereby resembling closely parkin-related disease. These findings confirm that recessive mutations in PINK1 cause early-onset parkinsonism and expand the associated clinical phenotype.
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- "Mutations in the mitochondrial serine/threonine kinase PTEN-induced putative kinase 1 (PINK1) correlate with disease incidence (Valente et al., 2004a). Many of these mutations cluster in the kinase domain of PINK1 and result in a non-functional protein (Hatano et al., 2004; Rohe et al., 2004; Valente et al., 2004a,b; Sha et al., 2010). Deficiencies of pink1 in Drosophila lead to changes in mitochondrial morphology, increased sensitivity to oxidative stress and reduced viability (Clark et al., 2006). "
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ABSTRACT: Protein-folding occurs in several intracellular locations including the endoplasmic reticulum and mitochondria. In normal conditions there is a balance between the levels of unfolded proteins and protein folding machinery. Disruption of homeostasis and an accumulation of unfolded proteins trigger stress responses, or unfolded protein responses (UPR), in these organelles. These pathways signal to increase the folding capacity, inhibit protein import or expression, increase protein degradation, and potentially trigger cell death. Many aging-related neurodegenerative diseases involve the accumulation of misfolded proteins in both the endoplasmic reticulum and mitochondria. The exact participation of the UPRs in the onset of neurodegeneration is unclear, but there is significant evidence for the alteration of these pathways in the endoplasmic reticulum and mitochondria. Here we will discuss the involvement of endoplasmic reticulum and mitochondrial stress and the possible contributions of the UPR in these organelles to the development of two neurodegenerative diseases, Parkinson's disease (PD) and Alzheimer's disease (AD).
Frontiers in Aging Neuroscience 04/2012; 4(article 5):5. DOI:10.3389/fnagi.2012.00005 · 4.00 Impact Factor
Available from: Anthony H Schapira
- "Several of the reported mutations of PINK1 are located in the kinase domain [38, 46–48] and altered phosphorylation of target proteins probably represents a key pathogenic mechanism. The phosphorylation of mitochondrial proteins is considered pivotal to the regulation of respiratory activity in the cell and to signalling pathways leading to apoptosis, as well as for other vital mitochondrial processes. "
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ABSTRACT: The identification of the etiologies and pathogenesis of Parkinson's disease (PD) should play an important role in enabling the development of novel treatment strategies to prevent or slow the progression of the disease. The last few years have seen enormous progress in this respect. Abnormalities of mitochondrial function and increased free radical mediated damage were described in post mortem PD brain before the first gene mutations causing familial PD were published. Several genetic causes are now known to induce loss of dopaminergic cells and parkinsonism, and study of the mechanisms by which these mutations produce this effect has provided important insights into the pathogenesis of PD and confirmed mitochondrial dysfunction and oxidative stress pathways as central to PD pathogenesis. Abnormalities of protein metabolism including protein mis-folding and aggregation are also crucial to the pathology of PD. Genetic causes of PD have specifically highlighted the importance of mitochondrial dysfunction to PD: PINK1, parkin, DJ-1 and most recently alpha-synuclein proteins have been shown to localise to mitochondria and influence function. The turnover of mitochondria by autophagy (mitophagy) has also become a focus of attention. This review summarises recent discoveries in the contribution of mitochondrial abnormalities to PD etiology and pathogenesis.
04/2011; 2011:159160. DOI:10.4061/2011/159160
Available from: Christopher Richie
- "Point mutations in the PTEN-induced kinase or PINK1 gene, a putative mitochondrial kinase at the PARK6 locus, are the second most frequently occurring cause of autosomal recessively inherited early-onset PD (Valente et al. 2001,2004; Hatano et al. 2004; Rogaeva et al. 2004; Rohe et al. 2004; Bonifati et al. 2005; Bender et al. 2006; Ibanez et al. 2006). PINK1 is present throughout the brain and localizes to mitochondria where it is thought to protect against mitochondrial dysfunction (Gandhi et al. 2006). "
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ABSTRACT: The identification of genes linked to neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) has led to the development of animal models for studying mechanism and evaluating potential therapies. None of the transgenic models developed based on disease-associated genes have been able to fully recapitulate the behavioral and pathological features of the corresponding disease. However, there has been enormous progress made in identifying potential therapeutic targets and understanding some of the common mechanisms of neurodegeneration. In this review, we will discuss transgenic animal models for AD, ALS, HD and PD that are based on human genetic studies. All of the diseases discussed have active or complete clinical trials for experimental treatments that benefited from transgenic models of the disease.
Journal of Neural Transmission 10/2010; 118(1):27-45. DOI:10.1007/s00702-010-0476-6 · 2.40 Impact Factor
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