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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Ataxin-3 is a 42 kDa, widely expressed protein that resides in both the nucleus and the cytoplasm of cells. It has been implicated in many aspects of intracellular protein quality control pathways that rely on ubiquitin, a small modifier protein. Ataxin-3 is a deubiquitinating enzyme (DUB) that cleaves ubiquitin from ubiquitinated substrates or polyubiquitin chains. Another proposed role for ataxin-3 is in the regulation of gene transcription.
Caenorhabditis elegans Aging is Associated with a Decline in Proteostasis
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
That is not to say, however, that the protein context in which a polyQ tract is embedded has no effect on aggregation and toxicity. In fact, a polyQ-containing fragment of the ataxin-3 protein (ataxin-3 CT) expressed in body wall muscle cells [27] or neurons [28], resulted in aggregation and toxicity. However, age-dependent changes in aggregation were observed for some models [24,25] but not others [27]. A list of polyQ proteins expressed in C. elegans is shown (Table 33.1).
Lipid Nanocarriers for Oligonucleotide Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Andreia F. Jorge, Santiago Grijalvo, Alberto Pais, Ramón Eritja
Stable nucleic acid lipid particles (SNALPs) were first developed in 2001 by Semple and colleagues and are considered an evolution of the cationic liposomes for delivering nucleic acids. Driven by this initial proposal, a lipid formulation composed of DO DAP/disaturated-phosphatidylcholine (DSPC)/chol/C16 mPEG2000 was devised to encapsulate LNA-modified anti-miR-21 or siRNA followed by postinsertion of micelles functionalised with chlorotoxin (CTX) to bind selectively to glioma cells. The assembled SNALPs displayed high encapsulation yields attributed to the complexation of ODNs with positive charged DODAP, a net surface charge close to neutrality and small sizes (<180 nm). Study outcomes described an increased cellular association and internalisation of CTX-targeted SNALPs by tumour cells, while sparing normal cells, increased tumour suppressor expression and caspase activity and a reduction in tumour cell proliferation [133]. The CTX-functionalised SNALPs with miR-21 were shown to accumulate preferentially within brain tumours and induce miR-21 silencing and decreased the tumour cell proliferation and tumour size, while showing no signs of systemic immunogenicity [134]. The same authors have used the same strategy to address Machado-Joseph disease (MJD) to deliver siRNA designed to target the ataxin-3 gene in neuronal cells. Initially, siRNA was encapsulated inside ceramide-PEGylated liposomes constituted by DODAP, DSPC and chol. In a second step, the resultant liposomes were involved by micelles made of DSPE-PEG functionalised with rabies virus glycoprotein-derived peptide RVG-r9. The intravenous administration of these SNALPs targeting neurons resulted in a significant knockdown of mutant ataxin-3 expression and aggregate formation [135].
Emerging therapeutic targets for narcolepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Marieke Vringer, Birgitte Rahbek Kornum
Behavioral data from mouse models offer some further insight into the functions of HcrtR1 and HcrtR2. Mice lacking the Hcrt peptide have a phenotype similar to human narcoleptic patients. The Hcrt-peptide-KO mice have fragmented sleep and wake states, cataplexy-like episodes of behavioral arrest during active wake, and SOREM periods [26]. Although these mice show a narcolepsy phenotype, the underlying cause is rather different from human narcolepsy since only the Hcrt gene is missing but the Hcrt neurons are still intact. In Hcrt/ataxin-3 (ATAX) mice, the development of narcolepsy symptoms is more similar to the human pathology. The toxic Ataxin-3 transgene causes apoptosis in Hcrt-containing cells resulting in degeneration of the neurons and symptom development starting around 6 weeks of age [5,58]. Gradual development of cataplexy and sleep fragmentation also occurs in the diphtheria toxin A (DTA) model. This model includes DTA expression in Hcrt neurons resulting in cell death under the control of doxycycline. These mice express the tetracycline-controlled transcriptional activator (tTA) exclusively in Hcrt neurons, which can induce DTA expression by binding to the tetracycline operator (TetO). However, tTA is unable to bind to TetO in the presence of doxycycline, and therefore Hcrt neuron degeneration can be controlled by adding or removing doxycycline from the diet [59]. Both the ATAX and the DTA model show fragmented sleep and wake states, behavioral cataplexy-like arrest and SOREM periods [58,59].
Polyglutamine spinocerebellar ataxias: emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Andreia Neves-Carvalho, Sara Duarte-Silva, Andreia Teixeira-Castro, Patrícia Maciel
The expanded proteins ataxin-3, 6, and 7 can be cleaved by endogenous proteases such as calpains and caspases, which can be used as therapeutic targets (Figure 2). The evidence supports the notion that the generation of short proteolytic-cleaved fragments of polyQ-containing proteins, which are highly toxic and aggregate quickly, contributes to pathogenesis – the ‘toxic fragment hypothesis’ (Reviewed in [3]). Ataxin-3 polyQ-containing fragments were reported to increase cytotoxicity and SDS-insoluble aggregate formation in cellular, C. elegans [98] and mouse models [54,147,148]. Intriguingly, patient brain tissue showed reduced calpastatin levels, an endogenous calpain inhibitor [149], and genetic approaches to inactivate calpain-1, overexpress calpastatin, or eliminate cleavage sites in ATXN3 were beneficial in several experimental models of SCA3 [147–151] Figure 2.
Uncovering the proteome response of murine neuroblastoma cells against low-dose exposure to saxitoxin
Published in Toxicology Mechanisms and Methods, 2018
Xiao Chen, Ye Sun, Haiyan Huang, Wei Liu, Panpan Hu, Xinfeng Huang, Fei Zou, Jianjun Liu
Besides, we found that some of these proteins are highly relevant to neurotoxicity. The interaction between 1433B and apoptosis signal-regulating kinase 1 (ASK1) inhibits the activity of ASK1 in inducing neuron apoptosis (Shinoda et al. 2003). Down-regulation of all isoforms of 14-3-3 proteins and up-regulation of 14-3-3 interacting proteins BAX and phosphorylation-ERK were observed in a kainic acid-induced excitotoxicity rat model (Smani et al. 2017). 14-3-3 protein was also reported to interact and stabilize ataxin-1 to mediate its neurotoxicity (Chen et al. 2003). ENO1 is a part of neuro-specific enolase dimer (NSE) which expresses in neuro-differentiation (Isgrò et al. 2015). NSE has been applied as an indicator of neuron injury to evaluate neurotoxicity of organic solvent (Züngün et al. 2013; Cliff et al. 2016). A functional study of 1433B and ENO1 should be taken out in the future to confirm their correlation to the saxitoxin exposure.