Fig. 7

Proposed model. A This study established a method that can rapidly and efficiently generate MSNs, by introducing a certain set of transcription factors, ASCL1/CTIP2/DLX1 or DLX2. B This study compared the capacity of four major neural subtypes including MSNs, in parallel, in modeling HD. Of note, MSN mimics the pathological features of HD more readily than other neural subtypes in a number of ways. For instance, MSNs exhibited stronger polyQ aggregation propensity and overexpression induced neurotoxicity, more severe BDNF/TrkB signaling dysfunction, greater susceptibility to BDNF withdrawal, and more severe NCT disturbances. This study further revealed that the nuclear lamina protein LMNB1 was greatly reduced in HD neurons and mislocalized to the cytoplasm and further extended to axons. Knockdown of HTT or treatment with KPT335, an orally SINE, effectively attenuated the pathological phenotypes and alleviated neuronal death caused by BDNF withdrawal. This study thus establishes an efficient method for obtaining MSNs and underscores the necessity of using high-purity MSNs to study HD pathogenesis, as MSNs performed best in mimicking multiple pathological features. On this basis, the MSN cellular platform shows increased potential for drug/chemical screening for the treatment of HD as well as for a variety of high-throughput analyses, such as multi-omics, mass spectrometry, next-generation sequencing, and biochemical assays