title: Pre-neurodegeneration of mitral cells in the pcd mutant mouse is associated with DNA damage, transcriptional repression, and reorganization of nuclear speckles and Cajal bodies.
abstract: DNA damage and impairment of its repair underlie several neurodegenerative diseases. The Purkinje cell degeneration (pcd) mutation causes the loss of Nna1 expression and is associated with a selective and progressive degeneration of specific neuronal populations, including mitral cells in the olfactory bulb. Using an in situ transcription assay, molecular markers for both nuclear compartments and components of the DNA damage/repair pathway, and ultrastructural analysis, here we demonstrate that the pcd mutation induces the formation of DNA damage/repair foci in mitral cells. Furthermore, this effect is associated with transcriptional inhibition, heterochromatinization, nucleolar segregation and the reorganization of nuclear speckles of splicing factors and Cajal bodies. The most significant cytoplasmic alteration observed was a partial replacement of rough endoplasmic reticulum cisternae by a larger amount of free ribosomes, while other organelles were structurally preserved. The tools employed in this work may be of use for the early detection of predegenerative processes in neurodegenerative disorders and for validating rescue strategies.
authors.affiliation: Laboratorio de Plasticidad Neuronal y Neurorreparación, Instituto de Neurociencias de Castilla y León, Universidad de Salamanca. Avd. Alfonso X el Sabio s/n, E-37007 Salamanca, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Valero
authors.forename: Maria T
authors.initials: MT
authors.lastname: Berciano
authors.forename: Eduardo
authors.initials: E
authors.lastname: Weruaga
authors.forename: Miguel
authors.initials: M
authors.lastname: Lafarga
authors.forename: José R
authors.initials: JR
authors.lastname: Alonso
mesh_terms: D000367:Age Factors; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002451:Cell Compartmentation; D016923:Cell Death / Q000235:genetics; D002466:Cell Nucleolus / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000473:pathology; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D007395:Interneurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008818:Mice, Neurologic Mutants; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009830:Olfactory Bulb / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology / Q000648:ultrastructure; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D053148:Caspase 3; D004791:Enzyme Inhibitors; D006657:Histones; D014157:Transcription Factors; C475961:gamma-H2AX protein, mouse