Underappreciated Roles of the Translocase of the Outer and Inner Mitochondrial Membrane Protein Complexes in Human Disease

Heinemeyer, Thea; Stemmet, Monique; Bardien, Soraya; Neethling, Annika

doi:10.1089/dna.2018.4292

Cited by 30 publications

(30 citation statements)

References 122 publications

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“…Recent genetic studies have also indicated that ApoE haplotypes are also related to PD and other neurodegenerative conditions and are responsible for the cognitive decline in these patients 8 . The role of TOMM40 in mitochondrial dysfunction is further supported by existing literature where a reduction in protein expression levels has been found in neurodegenerative diseases 34 . All these findings are consistent with the genetic effect of ApoE haplotypes being mediated by its ability to regulate the expression of TOMM40 and to induce (or avoid) mitochondrial dysfunction.…”

Section: Discussionsupporting

confidence: 54%

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the Apoe and Mapt Haplotypes

Kõks

Pfaff

Bubb

et al. 2021

Preprint

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Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s progression markers initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explain in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest (256) and smallest (-178) effect sizes measured as beta values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induces expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.

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Section: Discussionsupporting

confidence: 54%

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the Apoe and Mapt Haplotypes

Kõks

Pfaff

Bubb

et al. 2021

Preprint

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“…TRPM2 dysfunction linked to aberrant intracellular Ca 2+ accumulation and neuronal death has been implicated in AD. TRPM2 is involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression, a form of synaptic plasticity at glutamate synapses [101].…”

Section: The Pharmacogenomic Machinerymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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“…The TOM40 protein facilitates the import of approximately 1500 externally synthesised proteins and peptides into the mitochondria, and plays a key role in the mitophagy degradation pathway 7,8 . Altered or abnormally functioning TOM40, mediated by genetic changes or atypical protein expression, is thought to contribute to mitochondrial dysfunction and protein accumulation in Alzheimer's disease (AD) and PD 8 . This may occur through different mechanisms: 1) mitochondrial import impairment, which may prevent essential proteins and peptides from reaching their designated mitochondrial targets, or allow unwanted and mutant proteins to aggregate in the mitochondria; or 2) mitophagy disruption, which may enable damaged and malfunctioning mitochondria to accumulate.…”

Section: Introductionmentioning

confidence: 99%

“…Downstream of TOMM40 is apolipoprotein E (APOE), which is in strong linkage disequilibrium (LD), or non-randomly association, with TOMM40 9 . As a consequence of this linkage, polymorphisms in TOMM40 have been associated with a range of primarily cognition-based neurodegenerative diseases, including AD, frontotemporal dementia and dementia with Lewy bodies, as well as non-pathological ageing 8 . One of these variants is situated in intron 6 of TOMM40 and is a homopolymer of repeating thymine (T) nucleotides known as rs10524523 or '523' 9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…The translocase of outer mitochondrial membrane 40 homologue (TOMM40) gene encodes the pore-forming subunit (TOM40) of the protein-transport channels in the mitochondrial outer membrane, thus playing a fundamental role in mitochondrial functioning 6 . The TOM40 protein facilitates the import of approximately 1500 externally synthesised proteins and peptides into the mitochondria, and plays a key role in the mitophagy degradation pathway 7,8 . Altered or abnormally functioning TOM40, mediated by genetic changes or atypical protein expression, is thought to contribute to mitochondrial dysfunction and protein accumulation in Alzheimer's disease (AD) and PD 8 .…”

Section: Introductionmentioning

confidence: 99%

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The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease.

Bakeberg

Hoes

Gorecki

et al. 2020

Preprint

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Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not in the Australian cohort. Variation in the TOMM40 structural variant was not associated with PD risk, but may be a modifying factor for age of symptom onset in some PD populations, warranting further investigation.

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Underappreciated Roles of the Translocase of the Outer and Inner Mitochondrial Membrane Protein Complexes in Human Disease

Cited by 30 publications

References 122 publications

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the Apoe and Mapt Haplotypes

Transcript Variants of Genes Involved in Neurodegeneration Are Differentially Regulated by the Apoe and Mapt Haplotypes

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease.

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