Polyglutamine aggregation in<scp>H</scp>untington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation

Seidel, Kay; Siswanto, Sonny; Fredrich, Michaela; Bouzrou, Mohamed; Brunt, Ewout; Leeuwen, Fred W. van; Kampinga, Harm H.; Korf, Horst‐Werner; Rueb, Udo; Dunnen, den Wilfred

doi:10.1111/nan.12253

Cited by 43 publications

(40 citation statements)

References 53 publications

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“…These included basal ganglia-related extrapyramidal signs like dystonia [17,28], which should a priori be the consequence of the selective deterioration of striatal projecting neurons that are also affected in the human pathology [24,25]. As in humans, neurodegeneration does not appear to be associated with marked glial activation or inflammatory events [21].…”

Section: Discussionmentioning

confidence: 99%

“…Such responses have also been seen in autosomal-dominant spinocerebellar ataxias (SCAs; [15–17]), a group of inherited neurodegenerative disorders that mainly affect the cerebellum and its afferent/efferent structures, in which motor discoordination (“ataxia”) is the key symptom [18–21]. However, in most SCAs, and in particular SCA-3 or Machado-Joseph disease, the most prevalent of these rare disorders ([22] for review), neuronal malfunction/degeneration also occurs in extracerebellar structures like the brainstem, optic nerve, cortical areas and the basal ganglia ([23–25] for review). This explains why patients develop a broad-spectrum of neurological abnormalities, including primary cerebellar symptoms (e.g., progressive loss of motor coordination and abnormal gait: [24,26] for review) and non-cerebellar symptoms (e.g., muscle atrophy, oculomotor impairment, spasticity, and extrapyramidal signs such as rigidity and dystonia: [21,24,27] for review).…”

Section: Introductionmentioning

confidence: 99%

“…Such alterations were also found recently in a transgenic mouse model of SCA-3 [17], which reproduces many of the neurological and neuropathological signs of the disease [28]. This earlier study [17] concentrated on two key CNS structures (cerebellum and brainstem) closely related to the classic symptoms (motor incoordination, imbalance, gait anomalies) and neuropathological lesions (the loss of specific neuronal subpopulations in the dentate nucleus, Purkinje layer and pontine nuclei) observed in SCA-3 [25,26,29,30]. Hence, the pharmacological correction of such changes in endocannabinoid signaling may represent a promising therapeutic option for this disease.…”

Section: Introductionmentioning

confidence: 99%

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Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

et al. 2017

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Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

et al. 2017

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“…The age of onset may vary and is greatly, but not solely, dependent on the size of the expansion in the corresponding gene, with generally no significant difference in the age of onset between the sexes [47]. The average life span is approximately 10-20 years following diagnosis/symptomatic onset [48,49]. These diseases have selective neurodegeneration of areas such as the cerebellum, globus pallidus, pons and substantia nigra [2], along with progressive ataxia (incoordination and imbalance) leading to impairment of gait, speech and movement.…”

Section: Common Clinical Featuresmentioning

confidence: 99%

“…The ATXN3 gene, spanning a genomic region of approximately 48 kb (ENST00000558190.5) consists of 11 exons, with the start codon in exon 1 and the CAG repeat sequence located at the 5' end of exon 10 ( Table 2) [138]. Healthy individuals have up to 44 CAG repeats, whereas affected individuals possess 55-86 repeats, and the intermediate range of [45][46][47][48][49][50][51][52][53][54] repeats is generally associated with incomplete penetrance [75]. However, there is much conjecture as to exactly number of repeats that may be associated with disease, since as few as 51 repeats have been reported to be pathogenic in some cases.…”

Section: Molecular Geneticsmentioning

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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Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell‐type‐specific

Jansen

Hal

Kelder

et al. 2016

Glia

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Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions could be present in all brain cells. The effects of nuclear inclusion formation have been mainly studied in neurons, while the effect on glia has been comparatively disregarded. Astrocytes, microglia, and oligodendrocytes are glial cells that are essential for normal brain function and are implicated in several neurological diseases. Here we examined the number of nuclear mHTT inclusions in both neurons and various types of glia in the two brain areas that are the most affected in HD, frontal cortex, and striatum. We compared nuclear mHTT inclusion body formation in three HD mouse models that express either full‐length HTT or an N‐terminal exon1 fragment of mHTT, and we observed nuclear inclusions in neurons, astrocytes, oligodendrocytes, and microglia. When studying the frequency of cells with nuclear inclusions in mice, we found that half of the population of neurons contained nuclear inclusions at the disease end stage, whereas the proportion of GFAP‐positive astrocytes and oligodendrocytes having a nuclear inclusion was much lower, while microglia hardly showed any nuclear inclusions. Nuclear inclusions were also present in neurons and all studied glial cell types in human patient material. This is the first report to compare nuclear mHTT inclusions in glia and neurons in different HD mouse models and HD patient brains. GLIA 2016;65:50–61

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Polyglutamine aggregation inHuntington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation

Cited by 43 publications

References 53 publications

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

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

Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell‐type‐specific

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