Zhang, C.-L. | Search bioRxiv

bioRxiv2020

Rapid and efficient in vivo astrocyte-to-neuron conversion with regional identity and connectivity?

In vivo reprogramming of glia into functional neurons emerges as potential regeneration-based therapeutics for neural injuries or neurological diseases. Recent studies show that AAV-based manipulation of certain factors can rapidly and highly efficiently convert resident glia into functional neurons with brain region-specificity and precise connectivity. Using NEUROD1 as an example, we here show that the presumed astrocytes-converted neurons are essentially endogenous neurons in the adult mouse brain. AAV-mediated co-expression of NEUROD1 and a reporter indeed specifically, rapidly, and efficiently induces numerous reporter-labeled neurons. However, these neurons cannot be traced back to quiescent or reactive astrocytes by using stringent lineage-mapping strategies. Conversely, reporter-labeled neurons cannot be detected when NEUROD1 is strictly expressed in adult brain astrocytes. Through a retrograde labeling approach, our results rather reveal that endogenous neurons are the cell source for NEUROD1-induced reporter-labeled neurons. These results underline the indispensable value of stringent lineage-tracing strategies and beg for cautious interpretation of the in vivo reprogramming phenomena.

neuroscience↗

bioRxiv2020

Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia

DYT1 dystonia is a hereditary neurological disease caused by a heterozygous mutation in torsin A (TOR1A). While animal models provide insights into disease mechanisms, significant species-dependent differences exist since mice with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-derived motor neurons. These neurons with the heterozygous TOR1A mutation show markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport, whereas they lack the perinuclear "blebs" that are often observed in animal models. Importantly, we further uncover that the nuclear lamina protein LMNB1 is specifically dysregulated in expression and subcellular localization. LMNB1 downregulation can largely ameliorate all the cellular defects in DYT1 motor neurons. These results reveal the value of disease modeling with human neurons and provide novel molecular mechanisms underlying DYT1 dystonia and potentially other neurological diseases with impaired nucleocytoplasmic transport.

neuroscience↗