Recent insights into the networking of <i>CLN</i> genes and proteins in mammalian cells

Huber, Robert J.

doi:10.1111/jnc.15822

Cited by 5 publications

(3 citation statements)

References 139 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CLN proteins are distributed throughout the endomembrane system and regulate a variety of cellular processes related to ion homeostasis, autophagy, lipid metabolism, and protein trafficking [ 125 ]. To date, fourteen CLN proteins (CLN1-14) have been identified and characterized [ 126 , 127 ]. Among these, CLN6 and CLN8 localize to the membrane of the ER, where they regulate lysosomal enzyme recruitment and lysosome biogenesis [ 128 ], while CLN1, CLN2, CLN3, CLN5, and CLN10 localize to lysosomes and function as soluble enzymes [ 129 , 130 , 131 ].…”

Section: Lysosomal Ion Channelsmentioning

confidence: 99%

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System

Cen,

Hu,

Shen

et al. 2024

IJMS

View full text Add to dashboard Cite

Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl−, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets.

show abstract

Section: Lysosomal Ion Channelsmentioning

confidence: 99%

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System

Cen,

Hu,

Shen

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

“…CLN genes encode thirteen proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. Mutations in CLN genes cause a devastating form of neurodegeneration commonly known as Batten disease (Huber, 2023). It was recently shown that the ER/Golgi-localized ZIP7 colocalizes with CLN6 (Grubman et al, 2014).…”

Section: Zip Family In the Brainmentioning

confidence: 99%

Unlocking the brain’s zinc code: implications for cognitive function and disease

Sabouri,

Rostamirad,

Dempski

2024

Front. Biophys.

View full text Add to dashboard Cite

Zn2+ transport across neuronal membranes relies on two classes of transition metal transporters: the ZnT (SLC30) and ZIP (SLC39) families. These proteins function to decrease and increase cytosolic Zn2+ levels, respectively. Dysfunction of ZnT and ZIP transporters can alter intracellular Zn2+ levels resulting in deleterious effects. In neurons, imbalances in Zn2+ levels have been implicated as risk factors in conditions such as Alzheimer’s disease and neurodegeneration, highlighting the pivotal role of Zn2+ homeostasis in neuropathologies. In addition, Zn2+ modulates the function of plasma membrane proteins, including ion channels and receptors. Changes in Zn2+ levels, on both sides of the plasma membrane, profoundly impact signaling pathways governing cell development, differentiation, and survival. This review is focused on recent developments of neuronal Zn2+ homeostasis, including the impact of Zn2+ dyshomeostasis in neurological disorders, therapeutic approaches, and the increasingly recognized role of Zn2+ as a neurotransmitter in the brain.

show abstract

“…The localizations and functions of CLN proteins have been studied in several model organisms 20,21 . One such organism, the social amoeba Dictyostelium discoideum , has made important contributions to our understanding of CLN gene and protein networking and the roles of CLN genes in protein secretion 22–24 . On a broader level, D. discoideum is recognized as an exceptional model system for studying human lysosomal and trafficking diseases given the high degree of conservation of lysosomes and trafficking pathways between D. discoideum and humans 25 …”

Section: Introductionmentioning

confidence: 99%

Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD

Huber,

Kim,

Wilson‐Smillie

2024

Traffic

Self Cite

View full text Add to dashboard Cite

Ceroid lipofuscinosis neuronal 5 (CLN5) and cathepsin D (CTSD) are soluble lysosomal enzymes that also localize extracellularly. In humans, homozygous mutations in CLN5 and CTSD cause CLN5 disease and CLN10 disease, respectively, which are two subtypes of neuronal ceroid lipofuscinosis (commonly known as Batten disease). The mechanisms regulating the intracellular trafficking of CLN5 and CTSD and their release from cells are not well understood. Here, we used the social amoeba Dictyostelium discoideum as a model system to examine the pathways and cellular components that regulate the intracellular trafficking and release of the D. discoideum homologs of human CLN5 (Cln5) and CTSD (CtsD). We show that both Cln5 and CtsD contain signal peptides for secretion that facilitate their release from cells. Like Cln5, extracellular CtsD is glycosylated. In addition, Cln5 release is regulated by the amount of extracellular CtsD. Autophagy induction promotes the release of Cln5, and to a lesser extent CtsD. Release of Cln5 requires the autophagy proteins Atg1, Atg5, and Atg9, as well as autophagosomal‐lysosomal fusion. Atg1 and Atg5 are required for the release of CtsD. Together, these data support a model where Cln5 and CtsD are actively released from cells via their signal peptides for secretion and pathways linked to autophagy. The release of Cln5 and CtsD from cells also requires microfilaments and the D. discoideum homologs of human AP‐3 complex mu subunit, the lysosomal‐trafficking regulator LYST, mucopilin‐1, and the Wiskott–Aldrich syndrome‐associated protein WASH, which all regulate lysosomal exocytosis in this model organism. These findings suggest that lysosomal exocytosis also facilitates the release of Cln5 and CtsD from cells. In addition, we report the roles of ABC transporters, microtubules, osmotic stress, and the putative D. discoideum homologs of human sortilin and cation‐independent mannose‐6‐phosphate receptor in regulating the intracellular/extracellular distribution of Cln5 and CtsD. In total, this study identifies the cellular mechanisms regulating the release of Cln5 and CtsD from D. discoideum cells and provides insight into how altered trafficking of CLN5 and CTSD causes disease in humans.

show abstract

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

Cited by 5 publications

References 139 publications

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System

Pathological Functions of Lysosomal Ion Channels in the Central Nervous System

Unlocking the brain’s zinc code: implications for cognitive function and disease

Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD

Contact Info

Product

Resources

About