Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73

Abstract

Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPΔCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPΔCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPΔCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology.

Mutant Huntingtin impairs Ku70-mediated DNA repair

“…Altogether, the questions remain of whether genomic double-strand DNA is actually cleaved especially in neurons, whether DNA repair is affected in polyQ diseases, and which molecules mediate the DNA repair dysfunction. Hoshino et al, 2006). The genotoxic stress hypothesis seems consistent with previous notions that nuclear events initiate the polyQ disease pathology (Klement et al, 1998;Saudou et al, 1998;Katsuno et al, 2003).…”

“…Transcriptional repression in the HD pathology has been suggested by various research groups (Okazawa, 2003;Sugars and Rubinsztein, 2003;Hoshino et al, 2006). Accumulation of DNA damage causes transcriptional repression during transcriptioncoupled repair and induces apoptotic signals (for review see Sancar et al, 2004).…”

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

“…Interestingly, Suhr et al (2001) showed that p53 and SP1, a cofactor required for Puma induction, may be inhibited by sequestration into cytosolic or nuclear polyQ aggregates, perhaps reflecting a more widespread depression of specific transcriptional circuits. Indeed, a delayed, atypical form of nonapoptotic cell death attributable to transcriptional repression (TRIAD) was described in cortical, cerebellar, and striatal neurons and HD mice (Hoshino et al, 2006). The localization of p53-related factors remains to be studied in Q97-expressing neurons.…”

Mutant huntingtin impairs Ku70-mediated DNA repair

“…Transcriptional repression in the HD pathology has been suggested by various research groups (Okazawa, 2003;Sugars and Rubinsztein, 2003;Hoshino et al, 2006). Accumulation of DNA damage causes transcriptional repression during transcriptioncoupled repair and induces apoptotic signals (for review see Sancar et al, 2004).…”