mucolipidosis type
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2021 ◽  
Author(s):  
Taylor F. Minckley ◽  
Anna M. Dischler ◽  
Dylan H. Fudge ◽  
Ebrahim Ghazvini Zadeh ◽  
Wen-hong Li ◽  
...  

AbstractAccurate delivery of cargo over long distances through axonal transport requires precise spatiotemporal regulation. Here we discover that Zn2+, either released from lysosomes through TRPML1 or influx via depolarization, inhibits axonal transport. Zn2+-mediated inhibition is neither selective for cargo nor for cell type because elevated Zn2+ (IC50 ≈ 5 nM) reduces both lysosomal and mitochondrial motility in primary rat hippocampal neurons and HeLa cells. We further reveal that Zn2+ directly binds to microtubules and inhibits movement of kinesin motors. Loss of TRPML1 function, which causes Mucolipidosis Type IV (MLIV) disease, impairs lysosomal Zn2+ release, disrupts Zn2+-mediated regulation of axonal transport, and increases overall organellar motility. In addition, MLIV patient mutations in TRPML1 have decreased Zn2+ permeability, which parallels disease severity. Our results reveal that Zn2+ acts as a critical signal to locally pause axonal transport by directly blocking the progression of motor proteins on microtubules.Significance StatementDisruptions in proper axonal transport have been linked to neurodevelopmental and neurodegenerative diseases. Here we discover that activation of the lysosomal channel TRPML1 arrests lysosomal trafficking. Such lysosome self-regulation mechanism is mediated via TRPML1-mediated Zn2+, not Ca2+. We further reveal that Zn2+ acts as a critical brake signal to pause axonal transport locally by directly decorating microtubules and blocking the movement of motor proteins. Dysfunction of TRPML1, the genetic cause of Mucolipidosis type IV (MLIV), blocks lysosomal Zn2+ release, causing loss of fine-tuning of lysosomal motility. Overall, this study implicates the importance of Zn2+ signals and axonal transport in the pathology of MLIV and reveals new signaling roles for Zn2+ in regulating cell processes involved with microtubule-based transport.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Sapna Sandal ◽  
Sunita Bijarnia Mahay ◽  
Deepti Gupta ◽  
Renu Saxena ◽  
Jyotsna Verma ◽  
...  

Author(s):  
Emma J. Dogterom ◽  
Margreet A. E. M. Wagenmakers ◽  
Martina Wilke ◽  
Serwet Demirdas ◽  
Nicole M. Muschol ◽  
...  

2021 ◽  
Vol 27 ◽  
pp. 100747
Author(s):  
Parith Wongkittichote ◽  
Garland Michael Upchurch ◽  
Louis P. Dehner ◽  
Timothy Wood ◽  
Jorge L. Granadillo

2021 ◽  
Vol 132 ◽  
pp. S122
Author(s):  
David Gibson ◽  
Natario Couser ◽  
Vikram Brar ◽  
Rachel Li ◽  
Arun Kalra ◽  
...  

Ophthalmology ◽  
2021 ◽  
Vol 128 (4) ◽  
pp. 521
Author(s):  
Gilles C. Martin ◽  
Antoinette Bernabe-Gelot ◽  
Eric Gabison

2021 ◽  
Author(s):  
Andrea Hadjikyriacou ◽  
Sangeetha Iyer ◽  
Joshua D. Mast ◽  
Nina DiPrimio ◽  
John Concannon ◽  
...  

AbstractInvertebrate model organisms (the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) are valuable tools to bridge the gap between traditional in vitro discovery and preclinical animal models. Invertebrate model organisms are poised to serve as better disease models than 2D cellular monocultures for drug discovery, as well as easier and more cost-effective to scale up than 3D organoids/assembloids or co-cultures. A strength of model organisms is the opportunity to probe conserved biology such as lysosomal function and autophagy in a physiological setting. However, invertebrate models are not without pharmacokinetic and pharmacodynamic challenges, such as poor tissue penetration and confidence in a compound’s mechanism of action. To confront those challenges, we took advantage of the Novartis mechanism-of-action box (MoA Box), a compound library of well-annotated and drug-like chemical probes. Curious as to how the MoA Box, comprised of chemical probes optimized for mammalian targets, would fare in an invertebrate setting we screened the MoA Box across three different models of the lysosomal storage disease mucolipidosis Type IV (MLIV). MLIV is caused by mutations in the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1) resulting in hyper-acidic lysosomes and dysregulated autophagy. The overlap of screening hits from worm, fly, and patient fibroblast screens identified cyclin-dependent kinase (CDK) inhibition as an evolutionarily conserved disease modifier and potential drug repurposing strategy.Summary statementA trio of phenotypic screens across Drosophila, C. elegans, and H. sapiens models of mucolipidosis IV was performed and identified overlapping hits including cyclin-dependent kinase inhibitors.


Author(s):  
Cristina Bostan ◽  
Grant Mitchell ◽  
Benjamin Ellezam ◽  
Jean-François Soucy ◽  
Mona Harissi-Dagher ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lena Marie Westermann ◽  
Anke Baranowsky ◽  
Giorgia Di Lorenzo ◽  
Tatyana Danyukova ◽  
Jamie Soul ◽  
...  

AbstractSevere skeletal alterations are common symptoms in patients with mucolipidosis type II (MLII), a rare lysosomal storage disorder of childhood. We have previously reported that progressive bone loss in a mouse model for MLII is caused by an increased number of bone-resorbing osteoclasts, which is accompanied by elevated expression of the cytokine interleukin-6 (IL-6) in the bone microenvironment. In the present study we addressed the question, if pharmacological blockade of IL-6 can prevent the low bone mass phenotype of MLII mice. Since the cellular IL-6 response can be mediated by either the membrane-bound (classic signaling) or the soluble IL-6 receptor (trans-signaling), we first performed cell culture assays and found that both pathways can increase osteoclastogenesis. We then crossed MLII mice with transgenic mice expressing the recombinant soluble fusion protein sgp130Fc, which represents a natural inhibitor of IL-6 trans-signaling. By undecalcified histology and bone-specific histomorphometry we found that high circulating sgp130Fc levels do not affect skeletal growth or remodeling in wild-type mice. Most importantly, blockade of IL-6 trans-signaling did neither reduce osteoclastogenesis, nor increase bone mass in MLII mice. Therefore, our data clearly demonstrate that the bone phenotype of MLII mice cannot be corrected by blocking the IL-6 trans-signaling.


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