Genetic and biochemical studies of SNPs of the mitochondrial Aβ-degrading protease, hPreP

Pinho, Catarina Moreira; Björk, Behnosh F.; Alikhani, Nyosha; Bäckman, Hans G.; Eneqvist, Therese; Fratiglioni, Laura; Glaser, Elzbieta; Graff, Caroline

doi:10.1016/j.neulet.2009.11.075

Cited by 19 publications

(13 citation statements)

References 22 publications

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“…Accordingly, decreased proteolytic activity of PreP, as observed in the temporal lobe of AD brains (Alikhani et al , 2011), may contribute to disease progression. However, genetic variations in PITRM1 encoding PreP did not correlate with the risk of AD in >600 AD patients (Pinho et al , 2010). Therefore, despite compelling evidence for the degradation of mitochondrial Aβ by PreP, further studies are required to establish the pathogenic relevance of PreP to AD.…”

Section: Intramitochondrial Qc and Neurodegenerationmentioning

confidence: 99%

Mitochondrial quality control: a matter of life and death for neurons

2012

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Neuronal survival critically depends on the integrity and functionality of mitochondria. A hierarchical system of cellular surveillance mechanisms protects mitochondria against stress, monitors mitochondrial damage and ensures the selective removal of dysfunctional mitochondrial proteins or organelles. Mitochondrial proteases emerge as central regulators that coordinate different quality control (QC) pathways within an interconnected network of mechanisms. A failure of this system causes neuronal loss in a steadily increasing number of neurodegenerative disorders, which include Parkinson's disease, spinocerebellar ataxia, spastic paraplegia and peripheral neuropathies. Here, we will discuss the role of the mitochondrial QC network for neuronal survival and neurodegeneration.

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Section: Intramitochondrial Qc and Neurodegenerationmentioning

confidence: 99%

Mitochondrial quality control: a matter of life and death for neurons

2012

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“…The human presequence protease (hPreP) was recently shown to be the major mitochondrial A β -degrading enzyme. Genetic variation in the hPreP gene PITRM1 has been investigated by Pinho et al [93]. No genetic association was found between any of the SNPs and the risk for AD; however, functional analysis of four nonsynonymous SNPs in hPreP revealed a decreased activity compared to wild-type hPreP.…”

Section: Structural Genomics Of Alzheimer's Diseasementioning

confidence: 99%

Genomics of Dementia:APOE- andCYP2D6-Related Pharmacogenetics

Cacabelos

Martínez

Fernández‐Novoa

et al. 2012

International Journal of Alzheimer's Disease

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Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.

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“…The human presequence protease (hPreP) was recently shown to be the major mitochondrial Aβ-degrading enzyme. Genetic variation in the hPreP gene PITRM1 has been investigated by Pinho et al [88]. No genetic association between any of the SNPs and the risk for AD was found; however, functional analysis of four non-synonymous SNPs in hPreP revealed a decreased activity compared to wild-type hPreP .…”

Section: Genomics Of Dementiamentioning

confidence: 99%

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

et al. 2010

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About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.

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Genetic and biochemical studies of SNPs of the mitochondrial Aβ-degrading protease, hPreP

Cited by 19 publications

References 22 publications

Mitochondrial quality control: a matter of life and death for neurons

Mitochondrial quality control: a matter of life and death for neurons

Genomics of Dementia:APOE- andCYP2D6-Related Pharmacogenetics

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

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