Spinocerebellar ataxia

Klockgether, Thomas; Mariotti, Caterina; Paulson, Henry L.

doi:10.1038/s41572-019-0074-3

Cited by 456 publications

(459 citation statements)

References 242 publications

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“…Ttbk2 c.mut mice exhibited a shorter latency to fall compared to the littermate controls in each trial, for both the accelerating rotarod analysis as well as the steady speed rotarod analysis ( Figure 1A, 1B). These results indicate that Ttbk2 c.mut mice are impaired in their motor coordination after the loss of Ttbk2 throughout the adult mouse brain, consistent with motor deficits by observed in multiple mouse models of SCA (Lalonde and Strazielle, 2019) (Klockgether et al, 2019).…”

Section: Loss Of Ttbk2 From the Adult Brain Causes Sca-like Cerebellasupporting

confidence: 81%

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Bowie

Goetz

2019

Preprint

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Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. However, their function, particularly on neurons in the adult brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11).Here, we show that conditional knockout of Ttbk2 in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of human SCA11 including motor coordination deficits, loss of synaptic connections to Purkinje cells (PCs), and eventual loss of PCs. We also find that the Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 knockout, supporting disruption of ciliary signaling as a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining adult neuronal function, and offers novel insights into the mechanisms involved in neurodegeneration.

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Section: Loss Of Ttbk2 From the Adult Brain Causes Sca-like Cerebellasupporting

confidence: 81%

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Bowie

Goetz

2019

Preprint

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“…The extrapolated frequency of SCA48 in our reference cohort of study (overall 3.4%, about 23% amongst familial cases) suggests that this disorder would not be uncommon amongst SCAs, at least in Italy. Moreover, lack of evidence of founder mutations in our cohort supports that SCA48, like other dominant SCAs , might be identified worldwide.…”

Section: Discussionmentioning

confidence: 54%

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Lieto

Riso

Galatolo

et al. 2019

Euro J of Neurology

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Background and purpose Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive‐affective syndrome (CCAS), named SCA48. Methods Molecular screening was performed in a cohort of 235 unrelated patients with adult‐onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole‐exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico‐diagnostic findings were reviewed to define the phenotypic spectrum. Results Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions Our results support SCA48 as a significant cause of adult‐onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

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“…Most of the ataxias with a genetic origin are called spinocerebellar ataxias (SCAs), with more than 40 genetically distinct subtypes already identified, emphasizing the involvement of both the cerebellum and spinal cord, especially in SCAs with a CAG repeat expansion that encodes polyglutamine (polyQ) [4]. However, in some non-polyQ SCAs, the spinal cord is not primarily involved and the disease may arise in different anatomical structures, such as the basal ganglia or in peripheral nerves [5]. Moreover, several autosomal recessive or X-linked ataxias are also referred to as SCAs, with the addition of an R or X, respectively [6,7].…”

Section: Introductionmentioning

confidence: 99%

Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review

Benussi

Pascual‐Leone

Borroni

2020

IJMS

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Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.

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Spinocerebellar ataxia

Cited by 456 publications

References 242 publications

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review

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