Function – what a thing is for – and mechanism – how a thing's parts interact to make it work – are considered by cognitive psychologists and philosophers of science to be integrally related despite people's acute sensitivity to their differences. Here, we set out to better characterize lay adults' intuitions about functional and mechanistic knowledge (Study 1). Then, we use learning studies to investigate to what degree these intuitions accurately capture functional and mechanistic cognition (Studies 2, 3). While some intuitions (e.g., that mechanism is more difficult to learn than function) are supported by these learning studies, others (e.g., that function should precede mechanism in explanations) are not. Possible reasons for matches and mismatches are explored.

Developmental psychologists have often turned to children to clarify understanding of functional and mechanistic cognition. Here, we investigate children's epistemic inferences of function – what a thing is for – and mechanism – how a thing works. Children, like adults, believe a mechanism-knower knows more than a function-knower (Study 1). Yet, unlike adults, children do not expect that a mechanism-knower is also more likely to know function than a function-knower is to know mechanism (Study 2). Children's experience of learning function and mechanism of complex systems sheds light on this asymmetry; Children who are taught just mechanism can infer the complementary function, but, interestingly, children who are taught just function can likewise infer the complementary mechanism (Study 3). This paper considers the nature of children's epistemic intuitions and whether those beliefs are reflective of children's learning experience.

Background

Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP-Pgrn). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP-Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints.

Results

In vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP-Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease.

Conclusions

This study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP-Pgrn. Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD-Pgrn and other progranulin-related diseases.