Capturing schizophrenia-like prodromal symptoms in a spinocerebellar ataxia-17 transgenic rat

Amato, Davide; Canneva, Fabio; Nguyen, Huu Phuc; Bauer, Péter; Rieß, Olaf; Hörsten, Stephan von; Müller, Christian P.

doi:10.1177/0269881116675510

Cited by 5 publications

(4 citation statements)

References 75 publications

(86 reference statements)

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“…Findings on rat models supported a dysfunction of the monoamine systems also in SCA17, 25 and by analogy, we might speculate a role of it in the origin of self-injury.…”

Section: Discussionsupporting

confidence: 58%

Self-Injurious Behaviour in SCA17: A New Clinical Observation

Bonomo¹,

Latorre²,

Bhatia³

2019

Tremor and Other Hyperkinetic Movements

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Background Self-injurious behaviour is a clinical feature widely described in patients affected by mental retardation or psychiatric illnesses, such as psychosis or borderline personality disorder. 1 Among movement disorders, self-injury has been identified mostly in hyperkinesias, like chorea-acanthocytosis in which self-mutilating orolingual-biting is a well-recognised characteristic. 2 Nevertheless, such phenomenon can also be observed in Lesch-Nyhan syndrome (LNS), and it has recently been described in 6-pyruvoyl-tetrahydropterin synthase deficiency. 3,4 Here we report, for the first time, two cases of SCA17 presenting with self-injurious behaviour as part of their clinical symptomatology. The possible pathophysiological mechanisms underlying self-injury in hyperkinesias are further discussed. Case 1 A 66-year-old right-handed lady was diagnosed with Huntington's disease (HD)-like 4 disorder due to SCA17 mutation (43 CAG/CAA-repeats in TBP gene) at the age of 54. Disease onset was characterised by gait imbalance, falls and fidgetiness. Over the years, a progressive mood decline and cognitive deterioration accompanied the motor symptomatology. Concerning her family history, three of her siblings were similarly affected by generalised involuntary movements. On examination, she presented with motor impersistence on eyemovement assessment and tongue protrusion. Involuntary choreic movements affected the face and limbs. The gait was broad-based. Severity of ataxia was rated with the SARA scale (25/40). 5 Gait (4/8), stance (4/6) and speech (4/6) were significantly impaired; finger-chase test, nose-finger test, fast alternating movements and heel-shin test were as well severely affected (3/4); on sitting, there were slight difficulties with intermittent sway (1/4). Brain MRI disclosed a severe cerebellar volume loss. On the neuropsychological assessment, the most notable finding was a significant executive dysfunction. All the other domains assessed, including memory (MMSE 21/30), 6 visual perceptual skills, reading, naming, praxis and speed of information processing, were equally impaired.

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“…Findings on rat models supported a dysfunction of the monoamine systems also in SCA17, 25 and by analogy, we might speculate a role of it in the origin of self-injury.…”

Section: Discussionsupporting

confidence: 58%

Self-Injurious Behaviour in SCA17: A New Clinical Observation

Bonomo¹,

Latorre²,

Bhatia³

2019

Tremor and Other Hyperkinetic Movements

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“…To check whether such nonmotor deficits could be recapitulated in our mouse models, we performed a battery of behavioral tests. Prepulse inhibition of startle response measures sensorimotor gating (Braff and Geyer, 1990), and such a defect has been observed in a SCA17 transgenic rat model (Amato et al, 2016). A significant decrease in prepulse inhibition was found in 3-month-old germline-KI mice ( Fig.…”

Section: Generation and Characterization Of Neuronal Tbp-105q Ki (Cammentioning

confidence: 78%

Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17

Yang

Guo

et al. 2017

J. Neurosci.

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Spinocerebellar ataxia 17 (SCA17) is caused by polyglutamine (polyQ) repeat expansion in the TATA-binding protein (TBP) and is among a family of neurodegenerative diseases in which polyQ expansion leads to preferential neuronal loss in the brain. Although previous studies have demonstrated that expression of polyQ-expanded proteins in glial cells can cause neuronal injury via noncell-autonomous mechanisms, these studies investigated animal models that overexpress transgenic mutant proteins. Since glial cells are particularly reactive to overexpressed mutant proteins, it is important to investigate the role of glial dysfunction in neurodegeneration when mutant polyQ proteins are endogenously expressed. In the current study, we generated two conditional TBP-105Q knock-in mouse models that specifically express mutant TBP at the endogenous level in neurons or in astrocytes. We found that mutant TBP expression in neuronal cells or astrocytes alone only caused mild neurodegeneration, whereas severe neuronal toxicity requires the expression of mutant TBP in both neuronal and glial cells. Coculture of neurons and astrocytes further validated that mutant TBP in astrocytes promoted neuronal injury. We identified activated inflammatory signaling pathways in mutant TBP-expressing astrocytes, and blocking nuclear factor κB (NF-κB) signaling in astrocytes ameliorated neurodegeneration. Our results indicate that the synergistic toxicity of mutant TBP in neuronal and glial cells plays a critical role in SCA17 pathogenesis and that targeting glial inflammation could be a potential therapeutic approach for SCA17 treatment. Mutant TBP with polyglutamine expansion preferentially affects neuronal viability in SCA17 patients. Whether glia, the cells that support and protect neurons, contribute to neurodegeneration in SCA17 remains mostly unexplored. In this study, we provide both and evidence arguing that endogenous expression of mutant TBP in neurons and glia synergistically impacts neuronal survival. Hyperactivated inflammatory signaling pathways, particularly the NF-κB pathway, underlie glia-mediated neurotoxicity. Moreover, blocking NF-κB activity with small chemical inhibitors alleviated such neurotoxicity. Our study establishes glial dysfunction as an important component of SCA17 pathogenesis and suggests targeting glial inflammation as a potential therapeutic approach for SCA17 treatment.

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“…Although DAT expression has been found to change in animal models of antipsychotic responsivity, it cannot be assumed that the same mechanism applies in humans with schizophrenia. Indeed, data may differ across species as already shown with D 2 receptor binding (219) and dopamine synthesis (153). Therefore, why should this principle of species incompatibility not also apply for dopamine uptake?…”

Section: The Role Of Dat In Antipsychotic-resistant Schizophrenia: Lementioning

confidence: 95%

Hypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia

et al. 2019

Self Cite

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Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia.

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Capturing schizophrenia-like prodromal symptoms in a spinocerebellar ataxia-17 transgenic rat

Cited by 5 publications

References 75 publications

Self-Injurious Behaviour in SCA17: A New Clinical Observation

Self-Injurious Behaviour in SCA17: A New Clinical Observation

Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17

Hypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia

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