Cathepsin D deficiency delays central nervous system myelination by inhibiting proteolipid protein trafficking from late endosome/lysosome to plasma membrane

Abstract

This study aimed to investigate the role of cathepsin D (CathD) in central nervous system (CNS) myelination and its possible mechanism. By using CathD knockout mice in conjunction with immunohistochemistry, immunocytochemistry and western blot assays, the myelination of the CNS and the development of oligodendrocyte lineage cells in vivo and in vitro were observed. Endocytosis assays, real-time-lapse experiments and total internal reflection fluorescence microscopy were used to demonstrate the location and movement of proteolipid protein in oligodendrocyte lineage cells. In addition, the relevant molecular mechanism was explored by immunoprecipitation. The increase in Fluoromyelin Green staining and proteolipid protein expression was not significant in the corpus callosum of CathD−/− mice at the age of P11, P14 and P24. Proteolipid protein expression was weak at each time point and was mostly accumulated around the nucleus. The number of oligodendrocyte lineage cells (olig2+) and mature oligodendrocytes (CC1+) significantly decreased between P14 and P24. In the oligodendrocyte precursor cell culture of CathD−/− mice, the morphology of myelin basic protein-positive mature oligodendrocytes was simple while oligodendrocyte precursor cells showed delayed differentiation into mature oligodendrocytes. Moreover, more proteolipid protein gathered in late endosomes/lysosomes (LEs/Ls) and fewer reached the plasma membrane. Immunohistochemistry and immunoelectron microscopy analysis showed that CathD, proteolipid protein and VAMP7 could bind with each other, whereas VAMP7 and proteolipid protein colocalized with CathD in late endosome/lysosome. The findings of this paper suggest that CathD may have an important role in the myelination of CNS, presumably by altering the trafficking of proteolipid protein.

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

“…This could indicate a mild endosome maturation or fusion defect or could result from a trafficking defect back toward the plasma membrane. Such impaired proteolipid protein trafficking has been previously described to result from cathepsin D deficiency where phenotypically delayed central nervous system myelination was observed (Guo et al., ; Steinfeld et al., ) and hypomyelination was also noted in the brain MRI scans in Family 1 described here. However, PPP1R21 localization to early endosomes differs from cathepsin D localization to late endosomes/lysosomes, rendering such a retrograde trafficking defect as an unlikely major cause for the observed phenotype.…”

The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP

“…Evidence suggests that autophagy is one of the major mechanisms responsible for degradation of PLP (20,22). Several studies show that cathepsin D deficiency causes dysmyelination in the CNS of mice, accompanied by intracellular PLP accumulation and colocalization of PLP with LAMP1 (a lysosome marker) in oligodendrocytes (53,54). Herein, we showed that inactivation of PERK and ATF6α led to intracellular PLP accumulation and colocalization of PLP with ubiquitin, p62, and LAMP1 in mature oligodendrocytes of young adult mice.…”

Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice—An Animal Model of CLN10 Disease

“…The loss of RGCs might be a direct consequence of lysosomal dysfunction in these neurons, or might occur secondary to pathological alterations in visual target centres in the brain or the myelinated optic nerve and tract [ 44 , 95 , 96 ]. Of interest in this context is that the lack of CTSD resulted in reduced levels of proteolipid protein and myelin basic protein, impaired lipid homeostasis, delayed the maturation of oligodendrocytes and disrupted central nervous system myelination [ 97 , 98 ]. Together, data demonstrate a striking variability of the retinal pathologies at the structural and functional levels between different NCL forms and highlight the need for precise knowledge of the retinal pathology of each NCL form in order to develop effective treatments.…”