Taking out the garbage: cathepsin D and calcineurin in neurodegeneration

Abstract

Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca2⁺/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2⁺ homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease.

Keywords: Parkinson's disease; cathepsin D, calcineurin; endosomal sorting; lysosome; neurodegeneration; retromer; yeast; α-synuclein.

Figure 1

Interplay of cathepsin D (CatD), calcineurin and the retromer in health and neurodegenerative diseases. In healthy cells (left panel), a sophisticated and evolutionary conserved machinery governs the targeting and processing of CatD into lysosomes. CatD is an aspartyl protease important for the degradation of cargo delivered to lysosomes and thus contributes to cellular protein homeostasis. The retromer complex functions as a master regulator of endosomal sorting and facilitates correct trafficking and recycling of the mannose-6-phosphat (M6P) receptor, the major sorting receptor for CatD. We could show that at least basal levels of the Ca²⁺/calmodulin-dependent phosphatase calcineurin are required for efficient sorting of M6P and CatD in yeast, leading to speculations that calcineurin might contribute to the regulation of the retromer (Aufschnaiter et al., 2017). Blue arrows indicate pathways only identified in yeast so far; black arrows represent pathways established in yeast and higher eukaryotes; arrows with question marks reflect potential but unverified pathways. In neurodegenerative diseases (right panel), multiple proteins and pathogenic variants associated with these disorders (here illustrated for Parkinson's disease and Alzheimer's disease related gene products) have been shown to impair sorting processes of CatD via the M6P receptor and the retromer, ultimately resulting in reduced protease activity. This reduction in lysosomal degradative capacity is accompanied by morphological alterations, resulting in a reduced number of lysosomes and lysosomal enlargement. Dysregulation of calcineurin signalling is frequently observed in different neurodegenerative diseases and we reported an essential role of calcineurin in CatD-mediated cytoprotection against αSyn toxicity. In aggregate, a complex interplay of calcineurin, CatD and the retromer might essentially contribute to lysosomal function and thus neuronal health. Bar-headed lines represent pathways that are inhibited in the course of Parkinson's disease (red) or Alzheimer's disease (orange). Bar-headed lines with question marks reflect potential but unverified interferences.