A New Dominant Spinocerebellar Ataxia Linked to Chromosome 19q13.4-qter

Brkanac, Zoran; Bylenok, Laura; Fernandez, Magali; Matsushita, Mark; Lipe, Hillary; Wolff, John; Nochlin, David; Raskind, Wendy H.; Bird, Thomas D.

doi:10.1001/archneur.59.8.1291

Cited by 71 publications

(52 citation statements)

References 14 publications

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“…However, previous autopsy reports have shown no aggregation in SCA14 patient brains (1,44). The discrepancy might be due to the excessive expression of mutant γPKC in our experiments.…”

Section: Discussioncontrasting

confidence: 84%

Congo Red, an Amyloid-Inhibiting Compound, Alleviates Various Types of Cellular Dysfunction Triggered by Mutant Protein Kinase Cγ That Causes Spinocerebellar Ataxia Type 14 (SCA14) by Inhibiting Oligomerization and Aggregation

et al. 2010

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Abstract. Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant γPKC found in SCA14 is susceptible to aggregation that induces apoptotic cell death. Congo red is widely used as a histological dye for amyloid detection. Recent evidence has revealed that Congo red has the property to inhibit amyloid oligomers and fibril formation of misfolded proteins. In the present study, we examine whether Congo red inhibits aggregate formation and cytotoxicity of mutant γPKC. Congo red likely inhibits aggregate formation of mutant γPKC -green fluorescent protein (GFP) without affecting its expression level in SH-SY5Y cells. Congo red counteracts the insolubilization of recombinant mutant γPKC, suggesting that the dye inhibits aggregation of mutant γPKC by a direct mechanism. Congo red also inhibits aggregation and oligomerization of mutant γPKC-GFP in primary cultured cerebellar Purkinje cells. Moreover, the dye reverses the improper development of dendrites and inhibits apoptotic cell death in Purkinje cells that express mutant γPKC-GFP. These results indicate that amyloid-inhibiting compounds like Congo red may be novel therapeutics for SCA14.

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“…However, previous autopsy reports have shown no aggregation in SCA14 patient brains (1,44). The discrepancy might be due to the excessive expression of mutant γPKC in our experiments.…”

Section: Discussioncontrasting

confidence: 84%

Congo Red, an Amyloid-Inhibiting Compound, Alleviates Various Types of Cellular Dysfunction Triggered by Mutant Protein Kinase Cγ That Causes Spinocerebellar Ataxia Type 14 (SCA14) by Inhibiting Oligomerization and Aggregation

et al. 2010

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“…The first family with SCA14 shows anticipation of the age of onset and intermittent axial tremor in the early-onset patients , while the family with SCA16 occasionally has patients who develop head tremor (Miyoshi et al, 2001). A second family with SCA14 from the USA shows pure cerebellar ataxia with a variable age of onset, but do not develop intermittent axial myoclonus as seen in the Japanese family (Brkanac et al, 2002). Since the mutations responsible for SCA4, SCA14, and SCA16 are unknown, the exact frequencies of these disorders are also unknown at present.…”

Section: Dominant Scas Due To Unknown Mutationsmentioning

confidence: 98%

The hereditary spinocerebellar ataxias in Japan

Sasaki

Yabe

Tashiro

2003

Cytogenet Genome Res

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In Japan, multiple system atrophy (MSA) accounts for 40% of all spinocerebellar ataxias (SCAs) and hereditary disorders account for 30%. Among the latter, autosomal dominant disorders are common and recessive ataxias are rare. Although the frequency of SCA genotypes differs between geographic regions throughout Japan, SCA6, SCA3/MJD, and DRPLA are the three major disorders, while SCA7, SCA8, SCA10, SCA12, and SCA17 are infrequent or almost undetected. SCA1 predominantly occurs in the northern part of Japan. Overall, 20–40% of dominant SCAs are due to unknown mutations. From this cluster, pure cerebellar ataxias linked with the SCA4, SCA14, and SCA16 locus have been isolated. Among the recessive SCAs, patients with AVED and EAOH have been detected. However, FRDA associated with GAA repeat expansion in the frataxin gene has not been reported so far.

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“…SCAs with this mutation are also referred to as polyglutamine or CAG-repeat ataxias. (3) Non-coding triplet, quintuplet or hexaplet repeat expansions (SCA8, 10,12,31,36) [69, 86,90,103,150]. Although other SCAs have been successfully linked to distinct genetic loci, the disease gene and/or the causative mutations are still unknown (SCA4, 10,18,19,21,22,25,26,29,30,32,34) [38].…”

Section: Introductionmentioning

confidence: 99%

Brain pathology of spinocerebellar ataxias

et al. 2012

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The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. According to this categorization, ADCAs are divided into the spinocerebellar ataxias (SCAs) with a progressive disease course, and the episodic ataxias (EA) with episodic occurrences of ataxia. The prominent disease symptoms of the currently known and genetically defined 31 SCA types result from damage to the cerebellum and interconnected brain grays and are often accompanied by more specific extra-cerebellar symptoms. In the present review, we report the genetic and clinical background of the known SCAs and present the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages. Recent findings show that the brain is commonly seriously affected in the polyglutamine SCAs (i.e. SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and that the patterns of brain damage in these diseases overlap considerably in patients suffering from advanced disease stages. In the more rarely occurring non-polyglutamine SCAs, post-mortem neuropathological data currently are scanty and investigations have been primarily performed in vivo by means of MRI brain imaging. Only a minority of SCAs exhibit symptoms and degenerative patterns allowing for a clear and unambiguous diagnosis of the disease, e.g. retinal degeneration in SCA7, tau aggregation in SCA11, dentate calcification in SCA20, protein depositions in the Purkinje cell layer in SCA31, azoospermia in SCA32, and neurocutaneous phenotype in SCA34. The disease proteins of polyglutamine ataxias and some non-polyglutamine ataxias aggregate as cytoplasmic or intranuclear inclusions and serve as morphological markers. Although inclusions may impair axonal transport, bind transcription factors, and block protein quality control, detailed molecular and pathogenetic consequences remain to be determined.

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A New Dominant Spinocerebellar Ataxia Linked to Chromosome 19q13.4-qter

Cited by 71 publications

References 14 publications

Congo Red, an Amyloid-Inhibiting Compound, Alleviates Various Types of Cellular Dysfunction Triggered by Mutant Protein Kinase Cγ That Causes Spinocerebellar Ataxia Type 14 (SCA14) by Inhibiting Oligomerization and Aggregation

Congo Red, an Amyloid-Inhibiting Compound, Alleviates Various Types of Cellular Dysfunction Triggered by Mutant Protein Kinase Cγ That Causes Spinocerebellar Ataxia Type 14 (SCA14) by Inhibiting Oligomerization and Aggregation

The hereditary spinocerebellar ataxias in Japan

Brain pathology of spinocerebellar ataxias

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