Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson’s Disease

Plum, Sarah; Eggers, Britta; Helling, Stefan; Stepath, Markus; Theiß, Carsten; Leite, Renata; Molina, Mariana; Grinberg, Lea T.; Riederer, Peter; Gerlach, Manfred; May, Caroline; Marcus, Katrin

doi:10.3390/cells9122580

Cited by 18 publications

(13 citation statements)

References 94 publications

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“…This mutation had a high conservation score and it was classified as LP according to ACMG/AMP guidelines (Table 3 ), and it exhibited incomplete dominance in this family. MARS1 belongs to the aminoacyl-tRNA synthetase (AARS) gene group [ 17 ]. Aminoacyl-tRNA synthetases are important for protein synthesis [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response

et al. 2023

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Background While new genetic analysis methods are widely used in the clinic, few researchers have focused on trigeminal neuralgia (TN) with familial clustering (≥ 2 TN patients in one kindred family). Previous literature suggests that familial trigeminal neuralgia (FTN) may be associated with inherited genetic factors. To date, few next-generation sequencing studies have been reported for FTN. This study investigated the pathogenic mechanism of FTN by using whole-exome sequencing (WES) technology, which may enhance our understanding of human TN pathophysiology. Method We performed WES for 7 probands from families of FTN. Sanger sequencing was performed for two control groups (FTN family members group and nonfamilial TN subject group) to potentially identify new FTN-related gene mutations. In families where FTN probands carried potentially pathogenic gene mutations, the ribonucleic acid (RNA) of FTN probands and related family members, as well as nonfamilial TN patients were analysed by RNA sequencing (RNA-seq) to confirm differential gene expression. Results Seven probands were derived from 3 Chinese families. WES and Sanger sequencing identified MARS1 mutation c.2398C > A p.(Pro800Thr) in Family 1. MARS1 mutation was confirmed in 14/26 [53.8%] members of Family 1 in FTN family member group, while none of nonfamilial TN subjects had this MARS1 mutation. RNA-seq showed that 3 probands in Family 1 had higher expression of Fosl1 (Fos-like antigen 1) and NFE2 (Nuclear factor, erythroid 2) than 3 subjects in the nonfamilial TN subject group. Fosl1 and NFE2 are genes related to integrated stress response (ISR). Conclusion MARS1 mutations may cause chronic activation of ISR, contribute to ISR pathophysiological changes in FTN, and cause/accelerate peripheral nerve degeneration. The findings of this study can enrich our knowledge of the role of molecular genetics in TN in humans.

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Section: Discussionmentioning

confidence: 99%

MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response

et al. 2023

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“…Mass spectrometry was carried out as described [ 105 ]; a nanoHPLC analysis was performed on an UltiMate 3000 RSLC nano LC system (Thermo Fisher Scientific, Germany). Peptides were loaded on a capillary pre-column (Thermo Fisher Scientific, 100 μm × 2 cm, particle size 5 μm, pore size 100 Å) and afterwards onto an analytical C18 column (Thermo Fisher Scientific, 75 μm × 50 cm, particle size 2 μm, pore size 100 Å).…”

Section: Methodsmentioning

confidence: 99%

Desmin Knock-Out Cardiomyopathy: A Heart on the Verge of Metabolic Crisis

Elsnicová

Hornikova

Tibenská

et al. 2022

IJMS

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Desmin mutations cause familial and sporadic cardiomyopathies. In addition to perturbing the contractile apparatus, both desmin deficiency and mutated desmin negatively impact mitochondria. Impaired myocardial metabolism secondary to mitochondrial defects could conceivably exacerbate cardiac contractile dysfunction. We performed metabolic myocardial phenotyping in left ventricular cardiac muscle tissue in desmin knock-out mice. Our analyses revealed decreased mitochondrial number, ultrastructural mitochondrial defects, and impaired mitochondria-related metabolic pathways including fatty acid transport, activation, and catabolism. Glucose transporter 1 and hexokinase-1 expression and hexokinase activity were increased. While mitochondrial creatine kinase expression was reduced, fetal creatine kinase expression was increased. Proteomic analysis revealed reduced expression of proteins involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta-oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Thus, desmin deficiency elicits a secondary cardiac mitochondriopathy with severely impaired oxidative phosphorylation and fatty and amino acid metabolism. Increased glucose utilization and fetal creatine kinase upregulation likely portray attempts to maintain myocardial energy supply. It may be prudent to avoid medications worsening mitochondrial function and other metabolic stressors. Therapeutic interventions for mitochondriopathies might also improve the metabolic condition in desmin deficient hearts.

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“…An aliquot of synaptosomes from each sample was used for the quantification of the protein content using Bradford assay. Of note, discontinuous gradient-based subcellular fractionation has been shown to generate intact and enriched synaptic terminals from both human and rodent brain tissues by us and others [ 19 , 26 , 30 , 85 , 86 , 87 ].…”

Section: Methodsmentioning

confidence: 99%

Chemical Stimulation of Rodent and Human Cortical Synaptosomes: Implications in Neurodegeneration

Ahmad

Lladó

et al. 2021

Cells

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Synaptic plasticity events, including long-term potentiation (LTP), are often regarded as correlates of brain functions of memory and cognition. One of the central players in these plasticity-related phenomena is the α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR). Increased levels of AMPARs on postsynaptic membranes thus constitute a biochemical measure of LTP. Isolated synaptic terminals (synaptosomes) are an excellent ex vivo tool to monitor synaptic physiology in healthy and diseased brains, particularly in human research. We herein describe three protocols for chemically-induced LTP (cLTP) in synaptosomes from both rodent and human brain tissues. Two of these chemical stimulation protocols are described for the first time in synaptosomes. A pharmacological block of synaptosomal actin dynamics confirmed the efficiency of the cLTP protocols. Furthermore, the study prototypically evaluated the deficiency of cLTP in cortical synaptosomes obtained from human cases of early-onset Alzheimer’s disease (EOAD) and frontotemporal lobar degeneration (FLTD), as well as an animal model that mimics FLTD.

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Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson’s Disease

Cited by 18 publications

References 94 publications

MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response

MARS1 mutations linked to familial trigeminal neuralgia via the integrated stress response

Desmin Knock-Out Cardiomyopathy: A Heart on the Verge of Metabolic Crisis

Chemical Stimulation of Rodent and Human Cortical Synaptosomes: Implications in Neurodegeneration

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