The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

Kulczyńska-Przybik, Agnieszka; Mroczko, Piotr; Dulewicz, Maciej; Mroczko, Barbara

doi:10.3390/ijms22094630

Cited by 8 publications

(6 citation statements)

References 118 publications

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“…Given Rtn4’s shared characteristics with other known ER membrane-curving proteins (Zurek et al, 2011; Voeltz et al, 2006; Shibata et al, 2008; Hu et al, 2008), it is reasonable to think that this model could be generalized to other reticulons and the REEPs/DP1/Yop1p family of proteins. Additionally, considering the many links between ER structure and disease (Sharoar et al, 2016; Parlakgül et al, 2022), some implicating Rtn4 directly (Zheng et al, 2022; Zhang et al, 2021; Kulczyńska-Przybik et al, 2021b; Boghdadi et al, 2018; Kulczyńska-Przybik et al, 2021a; Chiurchiù et al, 2014), the results of this study may provide additional insight in this regard.…”

Section: Discussionmentioning

confidence: 92%

The nanoscale organization of reticulon 4 shapes local endoplasmic reticulum structurein situ

Fuentes

Marin

Baddeley

et al. 2023

Preprint

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The endoplasmic reticulums (ER) structure is directly linked to the many functions of the ER but its formation is not fully understood. We investigate how the ER-membrane curving protein reticulon 4 (Rtn4) localizes to and organizes in the membrane and how that affects local ER structure. We show a strong correlation between the local Rtn4 density and the local ER membrane curvature. Our data further reveal that the typical ER tubule possesses an elliptical cross-section with Rtn4 enriched at either end of the major axis. Rtn4 oligomers are linear-shaped, contain about five copies of the protein, and preferentially orient parallel to the tubule axis. Our observations support a mechanism in which oligomerization leads to an increase of the local Rtn4 concentration with each molecule increasing membrane curvature through a hairpin wedging mechanism. This quantitative analysis of Rtn4 and its effects on the ER membrane result in a new model of tubule shape as it relates to Rtn4.

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Section: Discussionmentioning

confidence: 92%

The nanoscale organization of reticulon 4 shapes local endoplasmic reticulum structurein situ

Fuentes

Marin

Baddeley

et al. 2023

Preprint

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“…Its function is mainly implicated in DNA binding or epigenetic modification, neuronal differentiation, and neurodegenerative diseases such as AD ( Recabarren and Alarcon, 2017 ). Considerable evidence suggests that all RTN proteins and receptor NgR are engaged in the pathology change of AD by regulating the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) function or APP processing, and thereby product amyloid β in the brain ( Kulczynska-Przybik et al, 2021 ). Previous studies have observed a significant decrease in RTN1 expression in the frontal cortex of AD patients ( Kim et al, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate genes associated with clinical onset of Alzheimer’s disease

et al. 2022

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Background and objectiveAlzheimer’s disease (AD) is the most common type of dementia, with its pathology like beta-amyloid and phosphorylated tau beginning several years before the clinical onset. The aim is to identify genetic risk factors associated with the onset of AD.MethodsWe collected three microarray data of post-mortem brains of AD patients and the healthy from the GEO database and screened differentially expressed genes between AD and healthy control. GO/KEGG analysis was applied to identify AD-related pathways. Then we distinguished differential expressed genes between symptomatic and asymptomatic AD. Feature importance with logistic regression analysis is adopted to identify the most critical genes with symptomatic AD.ResultsData was collected from three datasets, including 184 AD patients and 132 healthy controls. We found 66 genes to be differently expressed between AD and the control. The pathway enriched in the process of exocytosis, synapse, and metabolism and identified 19 candidate genes, four of which (VSNL1, RTN1, FGF12, and ENC1) are vital.ConclusionVSNL1, RTN1, FGF12, and ENC1 may be the essential genes that progress asymptomatic AD to symptomatic AD. Moreover, they may serve as genetic risk factors to identify high-risk individuals showing an earlier onset of AD.

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“…Initially, glia and T cells, especially M2 macrophages/microglia, and T helper (Th) 2 cells and regulatory T (Treg) cells have protective roles in maintaining motor neuron viability. At a later stage, cytotoxic M1 macrophages/microglia and proinflammatory Th1 and Th17 T cells become more active [ 164 , 165 , 166 , 167 , 168 ].…”

Section: Therapeutic Strategies For Als Targetsmentioning

confidence: 99%

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

Sever

Çi̇ftçi̇

DeMi̇rci̇

et al. 2022

IJMS

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Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

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The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

Cited by 8 publications

References 118 publications

The nanoscale organization of reticulon 4 shapes local endoplasmic reticulum structurein situ

The nanoscale organization of reticulon 4 shapes local endoplasmic reticulum structurein situ

Identification of candidate genes associated with clinical onset of Alzheimer’s disease

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

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