Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease)

Kim, William D.; Wilson-Smillie, Morgan L. D. M.; Thanabalasingam, Aruban; Lefrançois, Stéphane; Cotman, Susan L.; Huber, Robert J.

doi:10.3389/fcell.2022.812728

Cited by 16 publications

(14 citation statements)

References 321 publications

(600 reference statements)

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“…(ii) Autophagy. Dysregulation of autophagy has been suggested as a common mechanism in the pathogenesis of NCLs ( 54 ). We found that KCTD7-deficient cells display autophagic defects and are sensitive to nutrient deprivation–induced cell death.…”

Section: Discussionmentioning

confidence: 99%

KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses

et al. 2022

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Lysosomes are central organelles for cellular degradation and energy metabolism. Neuronal ceroid lipofuscinoses (NCLs) are a group of the most common neurodegenerative lysosomal storage disorders characterized by intracellular accumulation of ceroid in neurons. Mutations in KCTD7 , a gene encoding an adaptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, are categorized as a unique NCL subtype. However, the underlying mechanisms remain elusive. Here, we report various lysosomal and autophagic defects in KCTD7-deficient cells. Mechanistically, the CRL3-KCTD7 complex degrades CLN5, whereas patient-derived KCTD7 mutations disrupt the interaction between KCTD7-CUL3 or KCTD7-CLN5 and ultimately lead to excessive accumulation of CLN5. The accumulated CLN5 disrupts the interaction between CLN6/8 and lysosomal enzymes at the endoplasmic reticulum (ER), subsequently impairing ER-to-Golgi trafficking of lysosomal enzymes. Our findings reveal previously unrecognized roles of KCTD7-mediated CLN5 proteolysis in lysosomal homeostasis and demonstrate that KCTD7 and CLN5 are biochemically linked and function in a common neurodegenerative pathway.

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Section: Discussionmentioning

confidence: 99%

KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses

et al. 2022

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“…This is also the case with CLN3 disease. Research in various model organisms has highlighted the importance of CLN3 protein function in autophagy, indicating that it influences the expression and activity of lysosomal enzymes and modulates vesicular trafficking and autophagic degradation ( 23 ). It is not known whether Trehalose administration may also have a benefit on cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Cardiac magnetic resonance findings in neuronal ceroid lipofuscinosis: A case report

Todiere

Vecchia²,

Morales³

et al. 2022

Front. Neurol.

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Cardiac magnetic resonance imaging (MRI) is an essential tool for the study of hypertrophic cardiomyopathies (HCM) and for differentiating HCM from conditions with increased ventricular wall thickness, such as cardiac storage diseases. Although cardiac MRI is already used for the diagnosis and characterization of some forms of storage diseases involving the myocardium, it has not yet been used to study myocardial involvement in neuronal ceroid lipofuscinosis (NCL). Here, we describe comprehensive cardiac MRI findings in a patient with the CLN3 form of NCL showing basal inferior interventricular septal hypertrophy with maintained indexed LV mass within reference values and low T1-native values. MRI findings support a finding of abnormal storage material within the myocardium in CLN3 disease. We recommend the possible routine use of cardiac MRI for early diagnosis of cardiac involvement in CLN3 disease (also termed juvenile NCL) and to monitor the effects of emerging CLN3 therapies on the myocardium as well.

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“…RNA-seq identified DEGs in cln5 - cells associated with protein tagging, protein degradation, and autophagy, which aligns with studies from D. discoideum , mice, and humans linking the function of CLN5 to autophagy ( Best et al, 2017 ; Leinonen et al, 2017 ; Huber and Mathavarajah, 2018b ; Adams et al, 2019 ; Doccini et al, 2020 ; Basak et al, 2021b ; McLaren et al, 2021 ). Intriguingly, autophagy is dysregulated in many NCL subtypes ( Kim et al, 2022 ). Accumulated evidence suggests that autophagy and the ubiquitin-proteasome system work together to regulate protein degradation and operate in a compensatory manner when one of the pathways is inhibited ( Kocaturk and Gozuacik, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

Kim

Huber

2022

Front. Genet.

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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.

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Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease)

Cited by 16 publications

References 321 publications

KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses

KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses

Cardiac magnetic resonance findings in neuronal ceroid lipofuscinosis: A case report

An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

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