Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease

Alves, Sandro; Régulier, Etienne; Nascimento-Ferreira, Isabel; Hässig, Raymonde; Dufour, Noëlle; Koeppen, Arnulf H.; Carvalho, Ana Luı́sa; Simões, Sérgio; Lima, Maria C. Pedroso de; Brouillet, Emmanuel; Gould, Veronica Colomer; Déglon, Nicole; Almeida, Luís Pereira de

doi:10.1093/hmg/ddn106

Cited by 81 publications

(126 citation statements)

References 53 publications

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“…An shA 2A R (nts 419-437; see Figure 3) was inserted into a lentivector together with an enhanced green fluorescent protein (EGFP) reporter gene, as described previously (Alves et al, 2008). A hairpin designed to target the coding region of red fluorescent protein (nts 22-41) was used as an internal control (sh-control).…”

Section: Generation and Administration Of Lentiviral Vectorsmentioning

confidence: 99%

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

Simões

Machado

Gonçalves

et al. 2016

Neuropsychopharmacol

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The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A 2A receptors (A 2A Rs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A 2A Rs in the amygdala regulate synaptic plasticity and fear memory. We report that A 2A Rs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A 2A Rs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A 2A R (shA 2A R)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A 2A Rs in the amygdala after fear acquisition. The importance of A 2A Rs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A 2A R antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A 1 R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A 2A Rs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A 2A R polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A 2A Rs to manage fear-related pathologies.

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Section: Generation and Administration Of Lentiviral Vectorsmentioning

confidence: 99%

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

Simões

Machado

Gonçalves

et al. 2016

Neuropsychopharmacol

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“…Marked neuronal loss is also observed in the anterior horn of the spinal cord, and motor nuclei of the brainstem . Involvement of cerebellar cortex, autonomic ganglia and striatum were also confirmed in MJD Paulson et al, 1997b;Alves et al, 2008b). Recent data based on neuroimaging techniques (magnetic resonance imaging -MRI, and quantitative 3-D volumetry) confirmed a severe atrophy in MJD patients in the whole brainstem (midbrain, pons, and medulla), whole cerebellum, cerebellar hemispheres and cerebellar vermis, putamen and caudate nuclei (Schulz et al, 2010).…”

Section: Neuropathological Featuresmentioning

confidence: 85%

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Nóbrega¹,

Almeida²

2012

Spinocerebellar Ataxia

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“…Along with the common clinical characteristics, SCA3 is often distinguished by the evident pyramidal and extrapyramidal signs [136]. The selective neuronal loss seen in SCA3 is found in the cerebellar dentate neurons, basal ganglia and brainstem [9,34,137]. SCA3 is also known for its higher frequency of lid retraction and infrequent blinking, commonly known as "staring eyes" (Table 1) [67].…”

Section: Clinical Featuresmentioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease

Cited by 81 publications

References 53 publications

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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