Prolidase enzyme is required for extracellular matrix integrity and impacts on postnatal cerebellar cortex development

The extracellular matrix is essential for brain development, lamination, and synaptogenesis. In particular, the basement membrane below the pial meninx (pBM) is required for correct cortical development. The last step in the catabolism of the most abundant protein in pBM, collagen Type IV, requires prolidase, an exopeptidase cleaving the imidodipeptides containing pro or hyp at the C‐terminal end. Mutations impairing prolidase activity lead in humans to the rare disease prolidase deficiency characterized by severe skin ulcers and mental impairment. Thus, the dark‐like (dal) mouse, in which the prolidase is knocked‐out, was used to investigate whether the deficiency of prolidase affects the neuronal maturation during development of a brain cortex area. Focusing on the cerebellar cortex, thinner collagen fibers and disorganized pBM were found. Aberrant cortical granule cell proliferation and migration occurred, associated to defects in brain lamination, and in particular in maturation of Purkinje neurons and formation of synaptic contacts. This study deeply elucidates a link between prolidase activity and neuronal maturation shedding new light on the molecular basis of functional aspects in the prolidase deficiency. Prolidase is required for extracellular matrix organization that is fundamental for brain growth. Mutations in PEPD gene are responsible for a rare human autosomal recessive disorder called prolidase deficiency. Immunohistochemical techniques were conducted on sagittal sections of cerebellar cortex to investigate whether a lack of prolidase activity affects cortical maturation at two developmental ages: 10 and 60 days after birth. Aberrant cortical granule proliferation and migration was detected together with alterations in Purkinje neurons maturation and formation of synaptic contacts. Abbreviations: EGL, external granular layer; IGL, internal granular layer; ML, molecular layer, PL, Purkinje layer. Prolidase is required for collagen metabolism and extracellular matrix remodeling. The absence of prolidase impairs the pial basement membrane integrity. Cortical dysplasia altered Purkinje maturation and synaptogenesis in dal mice. Phosphorylated tau protein persists in Purkinje soma and dendrites of adult dal mice.