DYT6 Dystonia: A Neuropathological Study

Paudel, Reema; Li, Abi; Hardy, John; Bhatia, Kailash P.; Houlden, Henry; Holton, Janice L.

doi:10.1159/000440863

Cited by 19 publications

(14 citation statements)

References 22 publications

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“…This approach is proving useful in mouse models of other dystonias (DYT1 and 12), where compensatory developmental pathways are thought to prevent the later expression of dystonic posturing (53,66). Regardless, it is intriguing that our pathological findings-the reduction in D2R receptor levels (by raclopride binding), gliosis and the oligodendrocytic hypomyelination-are all observed in autopsy studies from human patients (67)(68)(69)(70).…”

Section: Discussionmentioning

confidence: 88%

Loss of the dystonia geneThap1leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes

Frederick¹,

Shah²,

Didonna

et al. 2018

Human Molecular Genetics

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Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss-of-function mutations in the zinc finger transcription factor THAP1. We have generated Thap1 knockout mice with a view to understanding its transcriptional role. While germ-line deletion of Thap1 is embryonic lethal, mice lacking one Thap1 allele-which in principle should recapitulate the haploinsufficiency of the human syndrome-do not show a discernable phenotype. This is because mice show autoregulation of Thap1 mRNA levels with upregulation at the non-affected locus. We then deleted Thap1 in glial and neuronal precursors using a nestin-conditional approach. Although these mice do not exhibit dystonia, they show pronounced locomotor deficits ref lecting derangements in the cerebellar and basal ganglia circuitry. These behavioral features are associated with alterations in the expression of genes involved in nervous system development, synaptic transmission, cytoskeleton, gliosis and dopamine signaling that link DYT6 to other primary and secondary dystonic syndromes.

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Section: Discussionmentioning

confidence: 88%

Loss of the dystonia geneThap1leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes

Frederick¹,

Shah²,

Didonna

et al. 2018

Human Molecular Genetics

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“…Mutations in the transcription factor, thanatos-associated protein domain containing apoptosis-associated protein 1 ( THAP1 ) result in DYT6 dystonia 17. A single report on tissue from two subjects with DYT6 dystonia, each with a different DYT6 mutation, did not reveal any evidence of significant neuronal loss 18. In addition, there was no evidence of ubiquitin immunoreactive inclusions in the midbrain.…”

Section: Resultsmentioning

confidence: 99%

Neuropathology of Dystonia

Sharma

2019

Tremor and Other Hyperkinetic Movements

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BackgroundDystonia is characterized by sustained or intermittent muscle contractions resulting in abnormal, often repetitive, movements, postures, or both. Neuropathologic research has been essential in understanding the etiology and disease progression of other movement disorders, including Parkinson’s disease and cerebellar ataxias. In the field of dystonia, however, research is stymied by the paucity of post-mortem tissue available and the phenotypic heterogeneity found in those with dystonia.MethodsA PubMed search was conducted using the term “neuropathology of dystonia”. The resulting list of references was limited to English-language human neuropathology articles. A total of 20 publications were retrieved and reviewed.ResultsHistorically, based on study of acquired forms of dystonia, lesions of the putamen and globus pallidus have been identified as causing dystonia. After the identification of genetic causes of dystonia and the study of limited tissue available from those cases, as well as findings from cases of isolated focal and segmental dystonia, there is evidence that brainstem cholinergic neurons and specific cell populations within the cerebellum also play a role in the pathophysiology of dystonia.DiscussionBased on limited available brain tissue, there is evidence that the pathophysiology of dystonia may involve a combination of dysfunction within neurons of the brainstem, cerebellum, putamen, and globus pallidus. In order to gain a better understanding of the pathophysiology of dystonia, a prospective, quantitative study in well-phenotyped subjects with different types of genetic and isolated dystonia is required.

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“…DYT6 is inherited in an autosomal dominant manner with reduced penetrance. Few brains from DYT6 patients have been examined and, to date, they do not exhibit any characteristic neuropathologic lesions [ 16 ]. Structural and functional neuroimaging in DYT6 manifesting and non-manifesting carriers (NMCs) demonstrates abnormalities in cerebello-thalamo-cortical and cortico-striato-pallido-thalamo-cortical pathways [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

et al. 2018

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Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1 [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding and protein-interaction domains, cause dystonia, DYT6. There is a unique, neuronal 50-kDa Thap1-like immunoreactive species, and Thap1 levels are auto-regulated on the mRNA level. However, THAP1 downstream targets in neurons, and the mechanism via which it causes dystonia are largely unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1 C54Y or ΔExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays were consistent with those enrichments, and the plasticity defects were partially corrected by salubrinal. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence in the pathophysiology of several forms of inherited dystonia.

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DYT6 Dystonia: A Neuropathological Study

Cited by 19 publications

References 22 publications

Loss of the dystonia geneThap1leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes

Loss of the dystonia geneThap1leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes

Neuropathology of Dystonia

Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

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