Trifluoperazine rescues human dopaminergic cells from wild-type α-synuclein-induced toxicity

Höllerhage, Matthias; Goebel, Joachim; Andrade, Anderson de; Hildebrandt, Tobias; Dolga, Amalia M.; Culmsee, Carsten; Oertel, Wolfgang H.; Hengerer, Bastian; Höglinger, Günter U.

doi:10.1016/j.neurobiolaging.2014.01.027

Cited by 52 publications

(83 citation statements)

References 64 publications

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“…For instance, the increase in autophagy flux induced by pimozide occurs along with a depression of phosphorylated tau in a transgenic mouse model of AD [260]. Again, the effects of two typical antipsychotics, trifluoperazine and haloperidol, on autophagy have been demonstrated indirectly [262,263]. For instance, haloperidol occludes huntingtin aggregation [262].…”

Section: A Step Forward About a Role Of Autophagy In The Pathophysmentioning

confidence: 99%

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

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The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

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Section: A Step Forward About a Role Of Autophagy In The Pathophysmentioning

confidence: 99%

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

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“…Therefore, it seems that in order for autophagy to exert its protective effects, a balance needs to be maintained to avoid neuronal death. a variety of animal models, and can aid the removal of aggregates associated with AD, PD, and HD [59,108,109] . In some cases, these treatments provide a degree of cognitive restoration [71,110] .…”

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confidence: 99%

Autophagic activity in neuronal cell death

2015

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As post-mitotic cells with great energy demands, neurons depend upon the homeostatic and waste-recycling functions provided by autophagy. In addition, autophagy also promotes survival during periods of harsh stress and targets aggregate-prone proteins associated with neurodegeneration for degradation. Despite this, autophagy has also been controversially described as a mechanism of programmed cell death. Instances of autophagic cell death are typically associated with elevated numbers of cytoplasmic autophagosomes, which have been assumed to lead to excessive degradation of cellular components. Due to the high activity and reliance on autophagy in neurons, these cells may be particularly susceptible to autophagic death. In this review, we summarize and assess current evidence in support of autophagic cell death in neurons, as well as how the dysregulation of autophagy commonly seen in neurodegeneration can contribute to neuron loss. From here, we discuss potential treatment strategies relevant to such cell-death pathways.

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“…Experiments on α-Syn overexpression were done in LUHMES cells, transduced with adenoviral vectors to overexpress human wild-type α-Syn and untransduced cells for control conditions respectively [27]. LUHMES cells were cultured in Nunclon Δ Surface (Nunc, Roskilde, Denmark) plastic cell culture flasks and multi-well plates pre-coated with 0.1 mg/ml poly-L-lysine and 5 μg/ml fibronectin (Sigma-Aldrich).…”

Section: α-Synuclein Overexpression In Luhmes Cellsmentioning

confidence: 99%

“…For differentiation the cells were transferred to multi-well plates at a density of 55,000/cm 2 in growth medium and 24 h after plating the medium was exchanged to differentiation medium, consisting of Dulbecco's modified Eagle's medium/F12 (Sigma-Aldrich), 1% N-2 supplement (Life Technologies), 1 μg/ml tetracycline (Sigma-Aldrich), 0.49 mg/ml dibutyryl cyclic AMP (Sigma-Aldrich), and 2 ng/ml GDNF (R&D Systems). Virus transduction was performed 48 h into the differentiation process at an multiplicity of infection of 5 as previously described [27].…”

Section: α-Synuclein Overexpression In Luhmes Cellsmentioning

confidence: 99%

Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease

Noelker

Lü

Höllerhage

et al. 2015

Journal of the Neurological Sciences

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Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57Bl/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP(+) (1-methyl-4-phenylpyridinium) or alpha-synuclein (α-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP-induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both α-Syn and MPP(+) induced toxicity in vitro. However, only CBE-induced enhancement of MPP(+) toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat. Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity.

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Trifluoperazine rescues human dopaminergic cells from wild-type α-synuclein-induced toxicity

Cited by 52 publications

References 64 publications

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Autophagic activity in neuronal cell death

Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease

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