How to treat Parkinson’s with astrocytes

Parkinson’s disease is characterized by neuronal loss in the brain’s substantia nigra region. What if another cell type, namely, astrocytes, could replace them?

The work of two research groups recently published ¹Zhou, H. et al. Cell 181, 590–603.e16 (2020).² shows that, at least in mice, transforming astrocytes (a non-neuronal cell type in the brain) into neurons is possible and that this change reverts partly the movement defects of Parkinson’s disease.

Most strategies to change the cell type involve the use of different transcription factors, as when producing induced pluripotent stem cells (iPSCs) which are derived from skin fibroblasts, but both teams did alter the neurons focusing on a single protein: PTB. This protein is an RNA-binding protein which inhibits neuronal differentiation

One of the teams targeted the proteins mRNA for degradation with shRNA while the other used CRISPR–CasRx, but both used them first in isolated astrocytes from mouse brains and then in vivo, using the same approach as they used in vitro.

And in all cases, the inhibition of this protein, PTB, led to transformation of astrocytes into neurons.

As a last step, they used these strategies in a Parkinson’s mouse model, where dopaminergic neurons are lost in the substantia nigra and therefore, in the striatum, where those neurons project, the amount of dopamine is low, leading to deficits in motor control.

Either inhibiting PTB in astrocytes in the substantia nigra or the striatum led to transformation into neuronal cell types, and what’s more, to an improvement in motor behaviour.

A possible reason why transforming astrocytes into neurons is at all possible just tweaking one single protein might be because they share a progenitor cell.

However, there are a number of limitations to the clinical application of these findings in Parkinson’s. First, the rate of transformation is still low (less than 40%); second, not only dopaminergic neurons are produced but other sort of neurons, and it is not clear in which proportions, and whether there are other side effects; and last, the majority of transformed neurons in the substantia nigra do not project to the striatum. Even though, motor improvements could be seen in Parkinson’s mice, so there is hope for the future.