Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

We used cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and experimentally evaluated the consequences of neuronal and astrocytic mHTT lowering on HD pathophysiology using cell-type specific RNA-seq The mHTT load was lowered in astrocytes and evaluated astrocytic and neuronal RNA-seq, in neurons and evaluated neuronal and astrocytic RNA-seq, in astrocytes brain-wide using PHP.eB AAVs, and in neurons using instrastriatal AAVs. Bulk-tissue (INPUT) and neuron-specific RNA-seq were performed in the striatum. A-Delta and N-Delta are control ZFP viruses. A-ZFP and N-ZFP are functional mHTT repressor viruses.