DNA repair protects neurons against spontaneous or disease-associated DNA 
damage. Dysfunctions of this mechanism underlie a growing list of 
neurodegenerative disorders. The Purkinje cell (PC) degeneration mutation causes 
the loss of nna1 expression and is associated with the postnatal degeneration of 
PCs. This PC degeneration dramatically affects nuclear architecture and provides 
an excellent model to elucidate the nuclear mechanisms involved in a whole array 
of neurodegenerative disorders. We used immunocytochemistry for histone variants 
and components of the DNA damage response, an in situ transcription assay, and 
in situ hybridization for telomeres to analyze changes in chromatin architecture 
and function. We demonstrate that the phosphorylation of H2AX, a DNA damage 
signal, and the trimethylation of the histone H4K20, a repressive mark, in 
extensive domains of genome are epigenetic hallmarks of chromatin in 
degenerating PCs. These histone modifications are associated with a large scale 
reorganization of chromatin, telomere clustering, and heterochromatin-induced 
gene silencing, all of them key factors in PC degeneration. Furthermore, ataxia 
telangiectasia mutated and 53BP1, two components of the DNA repair pathway, fail 
to be concentrated in the damaged chromatin compartments, even though the 
expression levels of their coding genes were slightly up-regulated. Although the 
mechanism by which Nna1 loss of function leads to PC neurodegeneration is 
undefined, the progressive accumulation of DNA damage in chromosome territories 
irreversibly compromises global gene transcription and seems to trigger PC 
degeneration and death.