A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition DOI Creative Commons
Rajesh Angireddy, Bhanu Chandra Karisetty,

Kaitlin Katsura

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract Background and Objectives TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the gene. Previous studies our lab others have implicated mTOR, autophagy, lysosomes, intracellular mRNA transport, however exact primary pathologic mechanism unknown. This gap has prevented development of targeted therapies. Methods We employed human neural progenitor cell line (NPC), ReNcell VM, which can differentiate into neurons astrocytes, to understand role mTORC1 activity neuronal autophagy cellular mechanisms pathology. used shRNA technology knockdown ReNcells. Results These data showed that loss did not inhibit neither NPC nor neurons. Additionally, analysis eight patient-derived cells knock down HeLa inhibition inconsistent across different patients types. ReNcells affected differentiation astrocytes. Specifically, defects are coupled cycle increased death during differentiation. RNAseq indicated downregulation several neurodevelopmental pathways. observed higher number LC3-positive vesicles soma neurites cells. Further, altered mitochondrial dynamics membrane potential NPC, found partial rescue with fission inhibitor mdivi- 1. Discussion work outlines new Human Cell Model for TBCK-related neurodegeneration essential health inhibitor. data, along illuminate provide possible novel therapeutic avenue patients.

Language: Английский

Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration DOI Creative Commons
Raffaella De Pace, Saikat Ghosh, Veronica H. Ryan

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(6), P. 1087 - 1102

Published: April 10, 2024

Abstract In neurons, RNA granules are transported along the axon for local translation away from soma. Recent studies indicate that some of this transport involves hitchhiking on lysosome-related vesicles. present study, we leveraged ability to prevent these vesicles into by knockout lysosome–kinesin adaptor BLOC-one-related complex (BORC) identify a subset axonal mRNAs depend transport. We found BORC causes depletion large group mainly encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. This results in mitochondrial defects eventually leads degeneration human induced pluripotent stem cell (iPSC)-derived mouse neurons. Pathway analyses depleted revealed mechanistic connection deficiency with common neurodegenerative disorders. These demonstrate mRNA is critical maintenance homeostasis its failure degeneration.

Language: Английский

Citations

27
The Trail of axonal protein Synthesis: Origins and current functional Landscapes DOI
Joaquín Garat, Andrés Di Paolo, Guillermo Eastman

et al.

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Structural basis of mRNA binding by the human FERRY Rab5 effector complex DOI Creative Commons
Dennis Quentin, Jan S. Schuhmacher, B.U. Klink

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(11), P. 1856 - 1871.e9

Published: June 1, 2023

The pentameric FERRY Rab5 effector complex is a molecular link between mRNA and early endosomes in intracellular distribution. Here, we determine the cryo-EM structure of human FERRY. It reveals unique clamp-like architecture that bears no resemblance to any known Rab effectors. A combination functional mutational studies while Fy-2 C-terminal coiled-coil acts as binding region for Fy-1/3 Rab5, both coiled-coils Fy-5 concur bind mRNA. Mutations causing truncations patients with neurological disorders impair or assembly. Thus, serves hub connecting all five subunits mediating via Rab5. Our study provides mechanistic insights into long-distance transport demonstrates particular closely linked previously undescribed mode RNA binding, involving domains.

Language: Английский

Citations

18
Localization of RNAs to the Mitochondria – Mechanisms and Functions DOI Open Access
Surbhi Sharma, Furqan M. Fazal

RNA, Journal Year: 2024, Volume and Issue: unknown, P. rna.079999.124 - rna.079999.124

Published: March 6, 2024

The mammalian mitochondrial proteome comprises over 1000 proteins, with the majority translated from nuclear-encoded messenger RNAs (mRNAs). Mounting evidence suggests many of these mRNAs are localized to outer membrane (OMM) in a pre-or co-translational state. Upon reaching surface, locally produce proteins that co-translationally imported into mitochondria. Here, we summarize various mechanisms cells employ localize RNAs, including transfer (tRNAs), OMM and recent technological advancements field study processes. While most early studies were carried out yeast, reveal RNA localization their regulation higher organisms. Various factors regulate this process, sequence elements, binding (RBPs), cytoskeletal motors, translation machinery. In review, also highlight role structures modifications discuss how features can alter properties RNAs. Finally, addition related function, involved other cellular processes OMM, those implicated innate immune response piRNA biogenesis. As impairment mRNA compromise future will undoubtedly expand our understanding investigate consequences mislocalization disorders, particularly neurodegenerative diseases, muscular dystrophies, cancers.

Language: Английский

Citations

8
Mechanistic insights into the basis of widespread RNA localization DOI
Marina Chekulaeva

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(7), P. 1037 - 1046

Published: July 1, 2024

Language: Английский

Citations

8
Linking transport and translation of mRNAs with endosomes and mitochondria DOI Creative Commons
Kira Müntjes, Senthil-Kumar Devan, Andreas S. Reichert

et al.

EMBO Reports, Journal Year: 2021, Volume and Issue: 22(10)

Published: Aug. 17, 2021

In eukaryotic cells, proteins are targeted to their final subcellular locations with precise timing. A key underlying mechanism is the active transport of cognate mRNAs, which in many systems can be linked intimately membrane trafficking. prominent example long-distance endosomal mRNAs and local translation. Here, we describe current highlights fundamental mechanisms process as well biological functions ranging from endosperm development plants fungal pathogenicity neuronal processes. Translation endosome-associated often occurs at cytoplasmic surface endosomes, a that needed for membrane-assisted formation heteromeric protein complexes accurate targeting proteins. Importantly, endosome-coupled translation encoding mitochondrial proteins, example, seems particularly important efficient organelle import regulating activity. essence, these findings reveal new loading newly synthesised onto endocytic membranes enabling intimate crosstalk between organelles. The novel link endosomes mitochondria adds an inspiring level complexity trafficking biology.

Language: Английский

Citations

40
Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites DOI Creative Commons
Stephanie Vrijsen, Céline Vrancx,

Mara Del Vecchio

et al.

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: June 21, 2022

Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset sporadic originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism commonly observed early preclinical stages of major NDs, including Parkinson's (PD) Alzheimer's (AD). Among the multitude underlying defective molecular mechanisms that have been suggested past decades, dysregulation inter-organellar communication through so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type subcellular organelle, to date, most focus has put on ER mitochondria given these compartments critical neuronal survival. Contributions MCSs, notably those with endolysosomes droplets emerging, supported as well by genetic studies, identifying genes functionally involved lysosomal In review, we summarize identity organelle interactome yeast mammalian cells, critically evaluate evidence supporting contribution disturbed general homeostasis taking PD AD examples.

Language: Английский

Citations

26
CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy DOI Creative Commons
Marta Zaninello, Tim Schlegel, Hendrik Nolte

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(22)

Published: May 29, 2024

Transporting and translating mRNAs in axons is crucial for neuronal viability. Local synthesis of nuclear-encoded mitochondrial proteins protects long-lived axonal mitochondria from damage; however, the regulatory factors involved are largely unknown. We show that CLUH, which binds encoding proteins, prevents peripheral neuropathy motor deficits mouse. CLUH enriched growth cone developing spinal motoneurons required their growth. The lack affects abundance target corresponding more prominently axons, leading to ATP cone. interacts with ribosomal subunits, translation initiation, ribosome recycling components preserves translation. Overexpression factor ABCE1 rescues mRNA defects, as well size, CLUH-deficient motoneurons. Thus, we demonstrate a role quality control translational regulation essential development long-term integrity function.

Language: Английский

Citations

5
FMRP regulates MFF translation to locally direct mitochondrial fission in neurons DOI Creative Commons
Adam R. Fenton, Ruchao Peng, Charles Bond

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(12), P. 2061 - 2074

Published: Nov. 15, 2024

Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile syndrome. FMRP disrupts mitochondrial health in neurons, but it unclear how supports homoeostasis. Here we demonstrate that granules are recruited to the midzone, where they mark fission sites axons and dendrites. Endolysosomal vesicles contribute granule positioning around mitochondria facilitate FMRP-associated via Rab7 GTP hydrolysis. Cryo-electron tomography real-time translation imaging reveal mitochondria-associated ribosome-rich structures serve as local protein synthesis. Specifically, promotes factor (MFF), selectively enabling replicative at midzone. Disrupting function dysregulates MFF perturbs dynamics, resulting increased peripheral an irregular distribution nucleoids. Thus, regulates precise control fission.

Language: Английский

Citations

5
Coupling axonal mRNA transport and local translation to organelle maintenance and function DOI Creative Commons
Jose Norberto S. Vargas, James N. Sleigh, Giampietro Schiavo

et al.

Current Opinion in Cell Biology, Journal Year: 2022, Volume and Issue: 74, P. 97 - 103

Published: Feb. 1, 2022

Neuronal homeostasis requires the transport of various organelles to distal compartments and defects in this process lead neurological disorders. Although several mechanisms for delivery axons dendrites have been elucidated, exactly how is orchestrated not well-understood. In review, we discuss recent literature supporting a novel paradigm - co-shuttling mRNAs with different membrane-bound organelles. This model postulates that tethering ribonucleoprotein complexes endolysosomes mitochondria allows spatiotemporal coupling organelle transcripts axons. Subcellular translation these "hitchhiking" may thus provide proximal source proteins required maintenance function

Language: Английский

Citations

20