Cln5 represents a new type of cysteine-based
            <i>S</i>
            -depalmitoylase linked to neurodegeneration

Luebben, Anna V.; Bender, Daniel A.; Becker, Stefan; Crowther, Lisa M.; Erven, Ilka; Hofmann, Kay; Söding, Johannes; Klemp, Henry Gerd; Bellotti, Cristina; Stäuble, Andreas; Qiu, Tian; Kathayat, Rahul S.; Dickinson, Bryan C.; Gärtner, Jutta; Sheldrick, George M.; Krätzner, Ralph; Steinfeld, Robert

doi:10.1126/sciadv.abj8633

Cited by 17 publications

(22 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study suggested regulation of S-depalmitoylation through palmitoyl thioesterase activity, leading to impairment in assembly and compartmentalisation of neuronal proteins and consequently affecting neuronal development. Variants affecting the palmitate binding pocket or the active site cause loss of thioesterase activity,3 but this putative mechanism does not explain the pathogenicity of most reported variants, including the p.Arg63Cys variant reported here.…”

mentioning

confidence: 55%

Ceroid lipofuscinosis type 5: novel pathogenic variants and unexpected phenotypic findings

Paiva

Pessoa

Nóbrega

et al. 2023

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

mentioning

confidence: 55%

Ceroid lipofuscinosis type 5: novel pathogenic variants and unexpected phenotypic findings

Paiva

Pessoa

Nóbrega

et al. 2023

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

“…These findings are consistent with work in D. discoideum and mammalian models of CLN5 disease that have linked the function of CLN5 to these cellular processes ( El Haddad et al, 2012 ; Schmiedt et al, 2012 ; Best et al, 2017 ; Leinonen et al, 2017 ; Adams et al, 2019 ; Doccini et al, 2020 ; McLaren et al, 2021 ; Yasa et al, 2021 ; Doccini et al, 2022 ). Previous work suggests that CLN5 functions as either a glycoside hydrolase or depalmitoylase ( Huber and Mathavarajah, 2018a ; Luebben et al, 2022 ). Here, comparative transcriptomics showed that loss of cln5 during growth alters the expression of genes that encode enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in CLN5 cause the CLN5 disease subtype of NCL (Schulz et a., 2013; Mole and Cotman, 2015 ). CLN5 is a soluble lysosomal and extracellular protein that is predicted to function as either a glycoside hydrolase or depalmitoylase ( Isosomppi et al, 2002 ; Hughes et al, 2014 ; Jules et al, 2017 ; Huber and Mathavarajah, 2018a ; Basak et al, 2021b ; Luebben et al, 2022 ). CLN5 has been linked to several cellular processes including, but not limited to, endosomal sorting, biometal homeostasis, sphingolipid metabolism, and autophagy ( El Haddad et al, 2012 ; Mamo et al, 2012 ; Grubman et al, 2014 ; Doccini et al, 2020 ; McLaren et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

Kim

Huber

2022

Front. Genet.

View full text Add to dashboard Cite

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 β-hexosaminidase activity, which aligns with previous work showing that D. discoideum Cln5 and human CLN5 can cleave the substrate acted upon by β-hexosaminidase. Finally, consistent with the differential expression of genes associated with proteasomal degradation in cln5- cells, we also observed elevated amounts of a proteasome subunit 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.

show abstract

“…To date, thirteen CLN proteins have been identified and characterized (PPT1/CLN1, TPP1/CLN2, CLN3, DNAJC5/CLN4, CLN5, CLN6, MFSD8/CLN7, CLN8, CTSD/CLN10, GRN/CLN11, ATP13A2/CLN12, CTSF/CLN13, KCTD7/CLN14) (Figure 1) (Butz et al, 2020; Mole & Cotman, 2015). Palmitoyl protein thioesterase 1 (PPT1), tripeptidyl peptidase 1 (TPP1), ceroid lipofuscinosis neuronal 5 (CLN5), cathepsin D (CTSD), and cathepsin F (CTSF) localize to lysosomes and function as soluble enzymes (Barrett, 1967; Hofmann et al, 1997; Huber & Mathavarajah, 2018; Isosomppi et al, 2002; Jerič et al, 2013; Luebben et al, 2022; Passini et al, 2006). They have also been detected extracellularly hinting that they may also play essential roles outside cells (Huber, 2021; Hughes et al, 2014; Isosomppi et al, 2002; Kaakinen et al, 2007; Kohan et al, 2005; Oörni et al, 2004; Poole et al, 1973).…”

Section: Introductionmentioning

confidence: 99%

“…A growing body of evidence suggests CLN proteins have shared functions, regulate similar processes, and participate in shared or convergent biological pathways (Huber, 2020). For example, both PPT1 and CLN5 have been reported to have depalmitoylase activity (PPT1: palmitoyl thioesterase, family of alpha/beta‐serine hydrolases; CLN5: cysteine‐based S‐depalmitoylase) (Cho et al, 2000; Luebben et al, 2022). In addition, significant overlap was detected in CLN3, CLN6, and CLN8 protein interactomes from mouse Neuro2A cells (Rechtzigel et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Recent insights into the networking of CLN genes and proteins in mammalian cells

Huber

2023

Journal of Neurochemistry

View full text Add to dashboard Cite

Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. In humans, mutations in CLN genes cause a devastating form of neurodegeneration called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Each CLN gene is associated with a specific subtype of the disease that differ from each other in severity and age of onset. The NCLs affect all ages and ethnicities worldwide but primarily affect children. The pathology underlying the NCLs is poorly understood, which has prevented the development of a cure or effective therapy for most subtypes of the disease. A growing body of literature supports the networking of CLN genes and proteins within cells, which aligns with the broadly similar cellular and clinical manifestations among the different subtypes of NCL. Here, all relevant literature is reviewed to provide a comprehensive overview of our current understanding of how CLN genes and proteins are networked in mammalian cells with an aim toward revealing new molecular targets for therapy development. Intriguingly, CLN gene and protein networking extends beyond the NCLs as recent work has linked several CLN genes and proteins to other forms of neurodegeneration such as Alzheimer's disease and Parkinson's disease. Thus, a deeper understanding of the pathways and cellular processes impacted by mutations in CLN genes will not only strengthen our knowledge of the pathological mechanisms underlying the NCLs but may also provide new insight into related forms of neurodegeneration.

show abstract

Cln5 represents a new type of cysteine-based S -depalmitoylase linked to neurodegeneration

Cited by 17 publications

References 66 publications

Ceroid lipofuscinosis type 5: novel pathogenic variants and unexpected phenotypic findings

Ceroid lipofuscinosis type 5: novel pathogenic variants and unexpected phenotypic findings

An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

Recent insights into the networking of CLN genes and proteins in mammalian cells

Contact Info

Product

Resources

About