In tandem, these papers catalogue a variety of phenotypes that were observed in HD-iPSC-derived neural progenitors and in medium spiny neurons. Both groups performed gene expression analysis to compare HD-iPSCs and their neuronal derivatives. The HD iPSC Consortium findings implicated genes that are involved in cell signaling, cell cycling, axon guidance and neuronal development as dysregulated in NSCs (Figure ). Importantly, medium CAG repeat expansions and longer CAG repeat expansions expressed most of these genes differently. An and co-workers performed transcript expression analysis, although they did this in iPSCs rather than in iPSC-derived NSCs. They observed that, in comparison with corrected controls, HD-iPSCs showed increased expression of genes that are involved in TGF-β signaling and decreased expression of genes involved in cadherin signaling (Figure ). Notably, the expression differences between the HD-iPSCs and corrected HD-iPSCs were of an order of magnitude less than those between non-related control iPSCs and HD-iPSCs.
Figure 1 HD-iPSCs, corrected iPSCs, and iPSC-derived neurons reveal key disease-associated phenotypes. An et al.  and the HD iPSC Consortium  generated HD-iPSC lines. An et al.  also generated corrected HD-iPSCs by homologous recombination and showed (more ...)
Comparison of the two studies also highlights the shared relevance of certain cellular and molecular phenotypes, such as cell death and mitochondrial dysfunction (Figure ). Initial studies had previously indicated that HD-iPSC-derived NSCs display increased caspase activity [4
], and that both HD-iPSCs and derived neurons exhibit increased lysosomal activity [5
]. An important finding that is shared by the two groups relates to defects in energy metabolism. Mitochondrial dysfunction, resulting in impaired cellular bioenergetics, is an emerging hallmark of HD [6
]. The HD iPSC Consortium reported decreased intracellular ATP levels in HD neural progenitor cells (NPCs), and An et al
. observed decreased oxygen consumption rates in HD-NSCs compared to corrected controls. Both of these phenotypes revealed defects in energy metabolism in the HD models, but the importance of mitochondrial dysfunction requires further investigation.
Another HD-associated phenotype that was observed by both groups is increased cell death. The HD iPSC Consortium used a variety of assays, including longitudinal survival tracking, nuclear condensation assays, and caspase 3/7 activation, to detect increased cell death in HD-NSCs and striatal-like derivatives. An and colleagues also observed CAG repeat-length-dependent cell death in similar assays. Both groups demonstrated a more severe cell death phenotype upon withdrawal of brain-derived neurotrophic factor (BDNF), adding to the mounting evidence to support a role for BDNF-associated toxicity in HD [7
]. BDNF is a secreted neurotrophin, which undergoes transcriptional repression in certain HD models, and there are indications that over-expression of BDNF can ameliorate the HD phenotype [8
]. Cell death in the striatum and cortex are hallmarks of HD; hence, this shared observation is significant, as it recapitulates in vitro
what is seen in vivo