Purkinje cells and their trees

“If a photographic plate under the center of a lens focused on the heavens is exposed for hours, it comes to reveal stars so far away that even the most powerful telescopes fail to reveal them to the naked eye. In a similar way, time and concentration allow the intellect to perceive a ray of light in the darkness of the most complex problem.”

Santiago Ramón y Cajal, 1897¹

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder. Because of the neurodegeneration of cerebellar Purkinje cells and brainstem neurons, patients with this disorder present with progressive ataxia, followed by bulbar dysfunction. The expansion of CAG repeats, encoding glutamine in the protein ataxin-1, is the genetic cause underlying SCA1. Long-standing collaborative studies between the research groups led by one of us (HYZ) and Harry T Orr (University of Minnesota, Minneapolis, MN, USA) have focused on understanding the drivers of dysfunction in Purkinje cells in SCA1.

Mutant ataxin-1 drives toxicity in Purkinje cells via its binding partner, the protein capicua, through a gain-of-function mechanism.² Although Purkinje cells are resilient to the loss of capicua or ataxin-1, they are very vulnerable to the enhanced function of the ataxin-1 and capicua complex, such that a slight reduction of ataxin-1 levels (about 20%) is enough to rescue the loss of Purkinje cells and revert the consequent ataxia in animal models.³

The development of the complex dendritic tree of Purkinje cells was meticulously studied by Cajal (appendix). In animal models of SCA1, loss of dendritic arbors precedes cell death and is accompanied by the onset of ataxia. Silencing the mutant gene restores the dendritic complexity in adult symptomatic animals, reverting their ataxia.⁴ This research gives hope that early intervention might improve outcomes in patients with SCA1.