dictyNews
Electronic Edition
Volume 48, number 22
October 28, 2022

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=========
Abstracts
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n altered transcriptome underlies cln5-deficiency phenotypes in 
Dictyostelium discoideum

William D. Kim and Robert J. Huber

Department of Biology, Trent University, Peterborough, Ontario, 
Canada


Frontiers in Genetics, accepted

Mutations in CLN5 cause a subtype of neuronal ceroid lipofuscinosis 
(NCL) called CLN5 disease. The NCLs, commonly referred to as 
Batten disease, are a family of neurodegenerative lysosomal storage 
diseases that affect all ages and ethnicities globally. Previous 
research showed that CLN5 participates in a variety of cellular 
processes. However, the precise function of CLN5 in the cell and the 
pathway(s) regulating its function are not well understood. In the 
model organism Dictyostelium discoideum, loss of the CLN5 homolog, 
cln5, impacts various cellular and developmental processes including 
cell proliferation, cytokinesis, aggregation, cell adhesion, and 
terminal differentiation. In this study, we used comparative 
transcriptomics to identify differentially expressed genes underlying 
cln5-deficiency phenotypes during growth and the early stages of 
multicellular development. During growth, genes associated with 
protein ubiquitination/deubiquitination, cell cycle progression, and 
proteasomal degradation were affected, while genes linked to protein 
and carbohydrate catabolism were affected during early development. 
We followed up this analysis by showing that loss of cln5 alters the 
intracellular and extracellular amounts of proliferation repressors 
during growth and increases the extracellular amount of conditioned 
medium factor, which regulates cAMP signalling during the early 
stages of development. Additionally, cln5- cells displayed increased 
intracellular and extracellular amounts of discoidin, which is 
involved in cell-substrate adhesion and migration. Previous work in 
mammalian models reported altered lysosomal enzyme activity due to 
mutation or loss of CLN5. Here, we detected altered intracellular 
activities of various carbohydrate enzymes and cathepsins during cln5- 
growth and starvation. Notably, cln5- cells displayed reduced 
beta-hexosaminidase activity, which aligns with previous work that 
showed that D. discoideum Cln5 and human CLN5 can cleave the 
substrate acted upon by beta-hexosaminidase. Finally, consistent with 
the differential expression of genes associated with proteasomal 
degradation in cln5- cells, we also observed elevated amounts of one 
of the proteasomal subunits and reduced proteasome 20S activity during 
cln5- growth and starvation. Overall, this study reveals the impact of 
cln5-deficiency on gene expression in D. discoideum, provides insight 
on the genes and proteins that play a role in regulating Cln5-dependent 
processes, and sheds light on the molecular mechanisms underlying 
CLN5 disease. 


Submitted by Robert Huber [[log in to unmask]]
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[End dictyNews, volume 48, number 22]