scholarly journals CLN5 and CLN3 function as a complex to regulate endolysosome function

2021 ◽  
Author(s):  
Seda Yasa ◽  
Etienne Sauvageau ◽  
Graziana Modica ◽  
Stephane Lefrancois
Keyword(s):  
Membrane Protein ◽  
Neurodegenerative Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Integral Membrane Protein ◽  
Cytosolic Protein ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Sorting ◽  
Sorting Receptor ◽  
Lysosomal Protein ◽  
Endocytic Proteins

CLN5 is a soluble endolysosomal protein whose function is poorly understood. Mutations in this protein cause a rare neurodegenerative disease, Neuronal Ceroid Lipofuscinosis. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein, retromer, is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an endolysosomal integral membrane protein whose mutations also result in Neuronal Ceroid Lipofuscinosis, RAB7A, and a subset of RAB7A effectors. Our data supports a model where CLN3 and CLN5 function as an endolysosomal complex regulating various functions.

scholarly journals CLN5 and CLN3 function as a complex to regulate endolysosome function

2020 ◽  
Author(s):  
Seda Yasa ◽  
Etienne Sauvageau ◽  
Graziana Modica ◽  
Stephane Lefrancois
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Integral Membrane Protein ◽  
Common Pathway ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Sorting ◽  
Summary Statement ◽  
Sorting Receptor ◽  
Golgi Network ◽  
Lysosomal Protein

AbstractCLN5 is a soluble endolysosomal protein that regulates the itinerary of the lysosomal sorting receptor sortilin. Mutations in this protein cause neuronal ceroid lipofuscinosis, a rare neurodegenerative disorder, and have also been associated with Alzheimer’s disease, suggesting functional defects in a common pathway. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an integral membrane protein, Rab7A and a subset of Rab7A effectors. Mutations in CLN3 are also a cause of neuronal ceroid lipofuscinosis. Our data supports a model where CLN3 and CLN5 function as an endolysosome complex regulating several endosomal functions.Summary StatementWe have previously demonstrated that CLN3 is required for efficient endosome-to-trans Golgi Network (TGN) trafficking of sortilin by regulating retromer function. In this work, we show that CLN5, which interacts with CLN3, regulates retromer function by modulating key interactions between CLN3, Rab7A, retromer, and sortilin. Therefore, CLN3 and CLN5 serve as endosomal switch regulating the itinerary of the lysosomal sorting receptors.

scholarly journals Neuronal ceroid lipofuscinosis related ER membrane protein CLN8 regulates PP2A activity and ceramide levels

2019 ◽  
Vol 1865 (2) ◽  
pp. 322-328 ◽  
Author(s):  
Babita Adhikari ◽  
Bhagya De Silva ◽  
Joshua A. Molina ◽  
Ashton Allen ◽  
Sun H. Peck ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Pp2a Activity ◽  
Ceroid Lipofuscinosis ◽  
Er Membrane

124. Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship

2009 ◽  
Vol 96 (2) ◽  
pp. S39
Author(s):  
Angela Schulz ◽  
Anne-Helene Lebrun ◽  
Stephan Storch ◽  
R∣schendorf Franz ◽  
Mia-Lisa Schmiedt ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Protein

scholarly journals Dipeptidyl-peptidase I does not functionally compensate for the loss of tripeptidyl-peptidase I in the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis

2008 ◽  
Vol 415 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Kwi-Hye Kim ◽  
Christine T. Pham ◽  
David E. Sleat ◽  
Peter Lobel
Keyword(s):  
Neurodegenerative Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Dipeptidyl Peptidase ◽  
The Body ◽  
Peripheral Tissues ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Tripeptidyl Peptidase ◽  
The Brain

LINCL (late-infantile neuronal ceroid lipofuscinosis) is a fatal neurodegenerative disease resulting from mutations in the gene encoding the lysosomal protease TPPI (tripeptidyl-peptidase I). TPPI is expressed ubiquitously throughout the body but disease appears restricted to the brain. One explanation for the absence of peripheral pathology is that in tissues other than brain, other proteases may compensate for the loss of TPPI. One such candidate is another lysosomal aminopeptidase, DPPI (dipeptidyl-peptidase I), which appears to have overlapping substrate specificity with TPPI and is expressed at relatively low levels in brain. Compensation for the loss of TPPI by DPPI may have therapeutic implications for LINCL and, in the present study, we have investigated this possibility using mouse genetic models. Our rationale was that if DPPI could compensate for the loss of TPPI in peripheral tissues, then its absence should exacerbate disease in an LINCL mouse model but, conversely, increased CNS (central nervous system) expression of DPPI should ameliorate disease. By comparing TPPI and DPPI single mutants with a double mutant lacking both proteases, we found that the loss of DPPI had no effect on accumulation of storage material, disease severity or lifespan of the LINCL mouse. Transgenic expression of DPPI resulted in a ∼2-fold increase in DPPI activity in the brain, but this had no significant effect on survival of the LINCL mouse. These results together indicate that DPPI cannot functionally compensate for the loss of TPPI. Therapeutic approaches to increase neuronal expression of DPPI are therefore unlikely to be effective for treatment of LINCL.

Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian Sibship

2009 ◽  
Vol 30 (5) ◽  
pp. E651-E661 ◽  
Author(s):  
Anne-Hélène Lebrun ◽  
Stephan Storch ◽  
Franz Rüschendorf ◽  
Mia-Lisa Schmiedt ◽  
Aija Kyttälä ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Protein

Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship

2008 ◽  
Vol 39 (05) ◽  
Author(s):  
AH Lebrun ◽  
S Storch ◽  
A Kyttällä ◽  
SE Mole ◽  
A Kohlschütter ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Protein

scholarly journals Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated CSPα mutants causes lipofuscin accumulation

2021 ◽  
Author(s):  
Yihong Ye ◽  
Juhyung Lee ◽  
Yue Xu ◽  
Layla Saidi ◽  
Miao Xu ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disease ◽  
Protein Secretion ◽  
Protein Quality ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Synaptic Proteins ◽  
Storage Material ◽  
Ceroid Lipofuscinosis ◽  
Control Functions ◽  
J Domain

Mutations in DNAJC5 (encoding the J domain-containing HSP70 co-chaperone CSPα) are associated with adult neuronal ceroid lipofuscinosis (ANCL), a dominant-inherited neurodegenerative disease featuring lysosome-derived autofluorescent storage material (AFSM) termed lipofuscin. Functionally, CSPα has been implicated in chaperoning synaptic proteins and in misfolding-associated protein secretion (MAPS), but how CSPα dysfunction causes lipofuscinosis and neurodegeneration is unclear. Here we report two distinct protein quality control functions of CSPα at endolysosomes and perinuclear vesicles, respectively. We show that the endolysosome-associated CSPα promotes microautophagy of misfolded clients, but is dispensable for MAPS. By contrast, the perinuclear-localized CSPα, regulated by a previously unknown CSPα interactor named CD98hc, is critical for MAPS but unneeded for microautophagy. Importantly, these processes are coupled by CSPα in a J-domain regulated manner. Uncoupling these two processes, as seen in cells lacking CD98hc or expressing ANCL-associated CSPα mutants, generates CSPα-containing AFSMs resembling NCL patient-derived lipofuscin, and also induces neurodegeneration in a Drosophila ANCL model. These findings suggest that blocking MAPS while allowing CSPα-mediated microautophagy disrupts lysosome homeostasis, causing CSPα-associated lipofuscinosis and neurodegeneration.

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