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1.
Article in English | WPRIM | ID: wpr-967115

ABSTRACT

The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are essential for maintaining both the structure and function of the brain. However, aging, cellular stress conditions, and genetic contributions cause disturbances in proteostasis and ribostasis that lead to protein misfolding, insoluble aggregate deposition, and abnormal ribonucleoprotein granule dynamics. In addition to neurons being primarily postmitotic, nondividing cells, they are more susceptible to the persistent accumulation of abnormal aggregates. Indeed, defects associated with the failure to maintain proteostasis and ribostasis are common pathogenic components of age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, the neuronal deposition of misfolded and aggregated proteins can cause both increased toxicity and impaired physiological function, which lead to neuronal dysfunction and cell death. There is recent evidence that irreversible liquid–liquid phase separation (LLPS) is responsible for the pathogenic aggregate formation of disease-related proteins, including tau, α-synuclein, and RNA-binding proteins, including transactive response DNA-binding protein 43, fused in sarcoma, and heterogeneous nuclear ribonucleoprotein A1. Investigations of LLPS and its control therefore suggest that chaperone/disaggregase, which reverse protein aggregation, are valuable therapeutic targets for effective treatments for neurological diseases. Here we review and discuss recent studies to highlight the importance of understanding the common cell death mechanisms of proteostasis and ribostasis in neurodegenerative diseases.

2.
Experimental Neurobiology ; : 550-563, 2018.
Article in English | WPRIM | ID: wpr-719049

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation.


Subject(s)
Humans , Amyotrophic Lateral Sclerosis , Axons , Drosophila , Exome , Fibroblasts , Histone Deacetylases , Microtubules , Mitochondria , Motor Neurons , Mutant Proteins , Mutation, Missense , Neurodegenerative Diseases , Neuromuscular Junction , Skin , Synapses
3.
Article in English | WPRIM | ID: wpr-171920

ABSTRACT

Rho small GTPases control multiple aspects of neuronal morphogenesis by regulating the assembly and organization of the actin cytoskeleton. Although they are negatively regulated by GTPase activating proteins (GAPs), the roles of RhoGAPs in the nervous system have not been fully investigated. Here we describe a characterization of Drosophila RhoGAP68F that is mainly expressed in the embryonic central nervous system. RNA in situ hybridization analysis showed that expression of RhoGAP68F is highly restricted to the embryonic brain and ventral nerve cord. Database search revealed that RhoGAP68F contains an N-terminal Sec14 domain and a C-terminal RhoGAP domain. Rho-GTP pull-down assay demonstrated that the RhoGAP domain of RhoGAP68F inactivates RhoA but not Rac1 or Cdc42 in HEK293 cells. In addition, expression of RhoGAP68F in NIH3T3 cells suppressed LPA-induced stress fiber formation, which is mediated by RhoA. Finally, neuronal overexpression of RhoGAP68F causes synaptic overgrowth at the larval neuromuscular junction (NMJ). Taken together, these results suggest that RhoGAP68F may play a role in synaptic growth regulation by inactivating RhoA.


Subject(s)
Actin Cytoskeleton , Actins , Brain , Central Nervous System , Drosophila , GTPase-Activating Proteins , HEK293 Cells , In Situ Hybridization , Monomeric GTP-Binding Proteins , Morphogenesis , Nervous System , Neuromuscular Junction , Neurons , RNA , Stress Fibers
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