Microcephaly-associated protein WDR62 supports purine metabolism by interacting with co-chaperone BAG2.

Abstract

Inherited mutations in the spindle pole-associated scaffold protein WDR62 cause autosomal recessive primary microcephaly. Previous research has characterised the roles of WDR62 in the regulation of spindle dynamics, cell division, and brain development. Here, we identify a new function of this protein in regulating purine metabolism. WDR62 interacts directly with BAG2, a co-chaperone of HSP70/90. Under stress conditions, WDR62 and BAG2 re-localise to cytoplasmic granules enriched for enzymes involved in purine synthesis (PFAS) and salvage (HPRT). In WDR62-deficient cells, purine synthesis is impaired, while purine deprivation leads to cytotoxicity and nucleoside accumulation. Furthermore, in these cells elevated BAG2 levels are linked to HPRT destabilisation, which can be reversed by BAG2 knockdown. Notably, microcephaly-associated WDR62 mutations disrupt interaction with BAG2 and fail to restore HPRT levels. In utero depletion of WDR62 or HPRT in the mouse neocortex causes premature delamination and migration of neural precursor cells. Interestingly, HPRT loss enhances self-renewal and proliferation of these precursors, contrasting with the reduced proliferation and precocious differentiation observed upon WDR62 loss. Our study identifies regulatory functions of WDR62 in purine metabolism that may contribute to primary microcephaly.