Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause?

Martı́nez-Menárguez, José A.; Tomàs, Mariona; Martínez-Martínez, Narcisa; Martínez‐Alonso, Emma

doi:10.3390/cells8070748

Cited by 65 publications

(67 citation statements)

References 151 publications

(198 reference statements)

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“…In our model (Fig. 7B), dispersed Golgi membranes arise after nicotine exposure through forward trafficking out of ERESs, not from uncoupling and/or fission of the GA stack, as has been proposed for the fragmentation associated with different neurodegenerative diseases (Machamer 2015, Martinez-Menarguez, Tomas et al 2019) and the formation of Golgi outposts (Quassollo, Wojnacki et al 2015). Unlike nocodazole-induced GA dispersal, the downstream effects of nicotine do not involve depolymerization of the microtubule network in either HEK cells (Fig.…”

Section: Extracellular Signaling Regulates the State Of The Gasupporting

confidence: 65%

Nicotine exposure and neuronal activity regulate Golgi membrane dispersal and distribution

Govind

Jeyifous

Russell

et al. 2020

Preprint

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How nicotine exposure produces long-lasting changes that remodel neural circuits with addiction is unknown. Here, we report that long-term nicotine exposure alters the trafficking of a4b2-type nicotinic acetylcholine receptors (a4b2Rs) by dispersing and redistributing the Golgi apparatus. In cultured neurons, dispersed Golgi membranes were distributed throughout somata, dendrites and axons. Small, mobile vesicles in dendrites and axons lacked standard Golgi markers and were identified by other Golgi enzymes that modify glycans. Nicotine exposure increased levels of dispersed Golgi membranes, which required a4b2R expression. Similar nicotine-induced changes occurred in vivo at dopaminergic neurons at mouse nucleus accumbens terminals, consistent with these events contributing to nicotine's addictive effects. Characterization in vitro demonstrated that dispersal was reversible, that dispersed Golgi membranes were functional, and that membranes were heterogenous in size, with smaller vesicles emerging from larger "ministacks", similar to Golgi dispersal induced by nocadazole. Protocols that increased cultured neuronal synaptic excitability also increased Golgi dispersal, without the requirement of a4b2R expression. Our findings reveal novel activity-and nicotine-dependent changes in neuronal intracellular morphology. These changes regulate levels and location of dispersed Golgi membranes at dendrites and axons, which function in local trafficking at subdomains.

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Section: Extracellular Signaling Regulates the State Of The Gasupporting

confidence: 65%

Nicotine exposure and neuronal activity regulate Golgi membrane dispersal and distribution

Govind

Jeyifous

Russell

et al. 2020

Preprint

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“…2) revealed that genes located in the Golgi apparatus and genes involved in cell structure are affected by variants identified in this study. Golgipathies and Golgi fragmentation are currently a matter of discussion for an influential role in neurodegenerative diseases and neurological development [34,35]. In summary, the polymorphisms affecting the genes discussed above substantially contribute to the explanation of the genetic architecture behind FP behavior.…”

Section: Discussionmentioning

confidence: 99%

Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes

et al. 2020

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Background Feather pecking (FP) is damaging behavior in laying hens leading to global economic losses in the layer industry and massive impairments of animal welfare. The objective of the study was to discover genetic variants and affected genes that lead to FP behavior. To achieve that we imputed low-density genotypes from two different populations of layers divergently selected for FP to sequence level by performing whole genome sequencing on founder and half-sib individuals. In order to decipher the genetic structure of FP, genome wide association studies and meta-analyses of two resource populations were carried out by focusing on the traits ‘feather pecks delivered’ (FPD) and the ‘posterior probability of a hen to belong to the extreme feather pecking subgroup’ (pEFP). Results In this meta-analysis, we discovered numerous genes that are affected by polymorphisms significantly associated with the trait FPD. Among them SPATS2L, ZEB2, KCHN8, and MRPL13 which have been previously connected to psychiatric disorders with the latter two being responsive to nicotine treatment. Gene set enrichment analysis revealed that phosphatidylinositol signaling is affected by genes identified in the GWAS and that the Golgi apparatus as well as brain structure may be involved in the development of a FP phenotype. Further, we were able to validate a previously discovered QTL for the trait pEFP on GGA1, which contains variants affecting NIPA1, KIAA1211L, AFF3, and TSGA10. Conclusions We provide evidence for the involvement of numerous genes in the propensity to exhibit FP behavior that could aid in the selection against this unwanted trait. Furthermore, we identified variants that are involved in phosphatidylinositol signaling, Golgi metabolism and cell structure and therefore propose changes in brain structure to be an influential factor in FP, as already described in human neuropsychiatric disorders.

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“…Further, the Ocrl1 puncta mentioned above colocalized poorly with TGN. It should be noted that a similar phenotype has been observed in neurological diseases such as Alzheimer's disease, ALS, epilepsy, Huntington's disease (24)(25)(26), and therefore might be relevant for the neurological component of LS.…”

Section: Discussionmentioning

confidence: 55%

“…Importantly, some of the phosphatase domain mutants tested produced fragmentation of the Golgi apparatus, a phenotype exclusive to this domain. This novel cellular phenotype has been associated with neurodegenerative diseases (24)(25)(26). Given that LS has a neurological component, we predict that this defect may play a role is disease pathogenesis.…”

Section: Introductionmentioning

confidence: 86%

Genotype & Phenotype in Lowe Syndrome: SpecificOCRL1patient mutations differentially impact cellular phenotypes

Ramadesikan¹,

Skiba²,

Lee³

et al. 2020

Preprint

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Lowe Syndrome (LS) is a lethal genetic disorder caused by mutations in the OCRL1 gene, which encodes the lipid 5’ phosphatase Ocrl1. Patients exhibit a characteristic triad of symptoms including eyes, brain and kidneys abnormalities with renal failure as the most common cause of death. Over 200 OCRL1 mutations have been identified in LS, but their specific impact on cellular processes is unknown. Despite observations of heterogeneity in LS patient symptoms, there is little understanding of the correlation between the genotype of patients and disease and/or cellular phenotypes.Here, we showed that different mutations had diverse effects on protein localization, stability and on triggering LS cellular phenotypes. In addition, mutations in specific domains imparted unique characteristics to the resulting mutated protein. We also propose that some mutations conformationally affect the 5’-phosphatase domain of the protein, resulting in additional phenotypes and loss of activity.This study is the first to show the differential effect of patient 5’-phosphatase mutations on cellular phenotypes and introduces a conformational disease component in LS. This work can provide a framework that can help stratify patients as well as provide a more accurate prognosis depending on the nature and location of the mutation in the OCRL1 gene and its effect on the biochemical activity of Ocrl1.

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Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause?

Cited by 65 publications

References 151 publications

Nicotine exposure and neuronal activity regulate Golgi membrane dispersal and distribution

Nicotine exposure and neuronal activity regulate Golgi membrane dispersal and distribution

Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes

Genotype & Phenotype in Lowe Syndrome: SpecificOCRL1patient mutations differentially impact cellular phenotypes

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