Neuronal and astrocytic contributions to Huntington’s disease dissected with zinc finger protein transcriptional repressors

Astrocytic contributions to Huntington's disease pathophysiology

“…130 ZFPs were thus used to cell-specifically lower mHTT locally within the striatum or in the whole brain using BBB-penetrant adeno-associated virus of the PHP.eB type 131 to molecularly dissect how astrocytes and neurons contribute to pathophysiology. 126 The consequences of mHTT lowering were assessed in astrocytes or neurons in turn for HD pathophysiology at the molecular, cellular, and behavioral levels in vivo. The major disease drivers were neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were mainly driven by neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling.…”

“…126 This study thus dissected cell-autonomous and non-cell-autonomous causal contributions of neurons and astrocytes to HD in vivo. 126 Remarkably, neuronal ZFPs were well tolerated, and resulted in profound neuron-specific mHTT lowering by 80% and rescue of HD model molecular, physiological, and behavioral phenotypes by >70%, results that support their development as therapeutics. 126 These data suggest that strategies that target neuronal rescue (e.g., by mHTT lowering) and restoration of the essential support and homeostatic functions of astrocytes, such as cholesterol, ion, and glutamate homeostasis, are likely to be the most effective way to treat HD.…”

“…Since HD is caused exclusively by a single known genetic defect, a recent study 126 utilized genetically encoded ZFPs 127,128 carrying a KRAB transcriptional repressor domain that have been engineered to be selective for the mutant HTT allele, 129,130 and which are in preclinical optimization stages for therapeutic development 130 . ZFPs were thus used to cell‐specifically lower mHTT locally within the striatum or in the whole brain using BBB–penetrant adeno‐associated virus of the PHP.eB type 131 to molecularly dissect how astrocytes and neurons contribute to pathophysiology 126 . The consequences of mHTT lowering were assessed in astrocytes or neurons in turn for HD pathophysiology at the molecular, cellular, and behavioral levels in vivo .…”

“…The consequences of mHTT lowering were assessed in astrocytes or neurons in turn for HD pathophysiology at the molecular, cellular, and behavioral levels in vivo . The major disease drivers were neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were mainly driven by neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling 126 . This study thus dissected cell‐autonomous and non–cell‐autonomous causal contributions of neurons and astrocytes to HD in vivo 126 .…”

“…The major disease drivers were neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were mainly driven by neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling 126 . This study thus dissected cell‐autonomous and non–cell‐autonomous causal contributions of neurons and astrocytes to HD in vivo 126 . Remarkably, neuronal ZFPs were well tolerated, and resulted in profound neuron‐specific mHTT lowering by 80% and rescue of HD model molecular, physiological, and behavioral phenotypes by >70%, results that support their development as therapeutics 126 .…”