Abstract
DYT1 dystonia is a severe form of young-onset dystonia caused by a mutation in the gene that encodes for the protein torsinA, which is thought to play a role in protein transport and degradation. We describe, for the first time to our knowledge, perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray in four clinically documented and genetically confirmed DYT1 patients but not in controls. The inclusions were located within cholinergic and other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephali and stained positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. No evidence of inclusion body formation was detected in the substantia nigra pars compacta, striatum, hippocampus, or selected regions of the cerebral cortex. We also noted tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and locus coeruleus in all four DYT1 dystonia cases, but not in controls. This study supports the notion that DYT1 dystonia is associated with impaired protein handling and the nuclear envelope. The role of the pedunculopontine and cuneiform nuclei, and related brainstem brainstem structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia [corrected]
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Amyloid beta-Peptides / metabolism
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Blotting, Western / methods
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Brain Stem / metabolism
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Brain Stem / pathology*
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Choline O-Acetyltransferase / metabolism
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Dystonia Musculorum Deformans / genetics
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Dystonia Musculorum Deformans / metabolism
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Dystonia Musculorum Deformans / pathology*
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Female
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Glial Fibrillary Acidic Protein / metabolism
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Humans
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Immunohistochemistry / methods
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Lamin Type A / metabolism
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Locus Coeruleus / metabolism
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Male
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Membrane Glycoproteins / metabolism
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Membrane Transport Proteins / metabolism
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Microtubule-Associated Proteins / metabolism
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism*
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Mutation
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Nerve Tissue Proteins / metabolism
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Postmortem Changes
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Protein Disulfide-Isomerases / metabolism
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RNA, Messenger / biosynthesis
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Serotonin Plasma Membrane Transport Proteins
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Synucleins
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Ubiquitin / metabolism
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tau Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Glial Fibrillary Acidic Protein
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Lamin Type A
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Membrane Glycoproteins
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Membrane Transport Proteins
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Microtubule-Associated Proteins
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Molecular Chaperones
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Nerve Tissue Proteins
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RNA, Messenger
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SLC6A4 protein, human
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Serotonin Plasma Membrane Transport Proteins
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Synucleins
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TOR1A protein, human
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Ubiquitin
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lamin C
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tau Proteins
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Choline O-Acetyltransferase
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Protein Disulfide-Isomerases