Maintenance of neuronal TDP-43 expression requires axonal lysosome transport DOI Creative Commons
Veronica H. Ryan,

Sydney Lawton,

Joel F. Reyes

et al.

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

Published: Oct. 1, 2024

Abstract TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate in neurons are not well understood. We generated Halo-TDP-43 knock-in iPSC line performed genome-wide CRISPR interference FACS-based screen to identify modifiers levels neurons. A meta-analysis our publicly available screens identified both specific hits present multiple screens, latter likely responsible for generic protein level maintenance. BORC, complex required anterograde lysosome transport, as modifier protein, mRNA, BORC loss led longer half-life other proteins, suggesting location is proper turnover. As such, function crucial maintaining

Language: Английский

The role of PINK1–Parkin in mitochondrial quality control DOI
Derek P. Narendra, Richard J. Youle

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(10), P. 1639 - 1651

Published: Oct. 1, 2024

Language: Английский

Citations

47
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

2
Cellular homeostatic responses to lysosomal damage DOI
Jingyue Jia, Suttinee Poolsup, Jaime Salinas-Chavira

et al.

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

1
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

7
Disruptions in axonal lysosome transport and its contribution to neurological disease DOI Creative Commons

Jean‐Michel Paumier,

Swetha Gowrishankar

Current Opinion in Cell Biology, Journal Year: 2024, Volume and Issue: 89, P. 102382 - 102382

Published: June 20, 2024

Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which long-lived, non-dividing highly polarized with specialized compartments such as axons dendrites distinct architecture, cargo, turnover requirements. In recent years, there has been a growing appreciation role played by axonal transport regulating neuronal development, its functioning. Perturbations optimal abundance leading either strong accumulations or dearth lysosomes both linked altered health this review we highlight how two regulators abundance, small GTPase Arl8 adaptor JIP3, aid maintaining alterations their levels activity could contribute neurodevelopmental neurodegenerative diseases.

Language: Английский

Citations

4
Maintenance of neuronal TDP-43 expression requires axonal lysosome transport DOI Open Access
Veronica H. Ryan,

Sydney Lawton,

Joel F. Reyes

et al.

Published: Jan. 6, 2025

TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate in neurons are not well understood. We generated Halo-TDP-43 knock-in iPSC line performed genome-wide CRISPR interference FACS-based screen to identify modifiers levels neurons. A meta-analysis our publicly available screens identified both specific hits present multiple screens, latter likely responsible for generic protein level maintenance. BORC, complex required anterograde lysosome transport, as modifier protein, mRNA, BORC loss led longer half-life other proteins, suggesting location is proper turnover. As such, function crucial maintaining

Language: Английский

Citations

0
Maintenance of neuronal TDP-43 expression requires axonal lysosome transport DOI Open Access
Veronica H. Ryan,

Sydney Lawton,

Joel F. Reyes

et al.

Published: Jan. 6, 2025

TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate in neurons are not well understood. We generated Halo-TDP-43 knock-in iPSC line performed genome-wide CRISPR interference FACS-based screen to identify modifiers levels neurons. A meta-analysis our publicly available screens identified both specific hits present multiple screens, latter likely responsible for generic protein level maintenance. BORC, complex required anterograde lysosome transport, as modifier protein, mRNA, BORC loss led longer half-life other proteins, suggesting location is proper turnover. As such, function crucial maintaining

Language: Английский

Citations

0
Multi-organelle-mediated mRNA localization in neurons and links to disease DOI Creative Commons

Vance K. Bauer,

Max Koppers

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102332 - 102332

Published: March 7, 2025

Brain function requires precise spatiotemporal regulation of the neuronal proteome. To allow adaptation proteome in distal outposts neurons, mRNAs are transported into neurites for localized translation. This mRNA localization and local translation is crucial neuron maintenance, dysregulation these processes can contribute to neurological disease. Recently, organelles have emerged as key players regulating dendrites axons. In this review, we discuss current evidence open questions organelle-mediated localization. We highlight an emerging model which multiple create orchestrate a subcellular microenvironment that support selective seems essential maintaining organellar health, mutations many involved proteins lead various disorders.

Language: Английский

Citations

0
TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons DOI Creative Commons
Marco Flores‐Méndez,

Jesus A Tintos-Hernández,

Leonardo Ramos-Rodriguez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

ABSTRACT Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms progressive encephalopathy and motor neuron disease. Yet, physiological role protein remains unclear. We report human TBCKE model, derived from iPSCs homozygous for Boricua variant (p.R126X). Using unbiased proteomic analyses neurons, we find interacts with PPP1R21, C12orf4, Cryzl1, consistent being part FERRY mRNA transport complex. Loss leads to depletion C12ORF4 levels across multiple cell types, suggesting may play regulating at least some members preferentially, not exclusively, localizes surface endolysosomal vesicles colocalize lysosomes. Furthermore, TBCK-deficient neurons have reduced content axonal compartment relative soma. lysosomal dynein/dynactin adapter JIP4, which functionally exhibiting striking retrograde trafficking defects. Hence, our work reveals mediate mRNA, particularly along lysosomes compartments. TBCK-deficiency compartment-specific defects likely contribute preferential susceptibility neurodegeneration.

Language: Английский

Citations

0
Decoding the complex journeys of RNAs along neurons DOI Creative Commons
Jenna L. Wingfield, Sathyanarayanan V. Puthanveettil

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(7)

Published: April 10, 2025

Abstract Neurons are highly polarized, specialized cells that must overcome immense challenges to ensure the health and survival of organism in which they reside. They can spread over meters persist for decades yet communicate at sub-millisecond millimeter scales. Thus, neurons require extreme levels spatial-temporal control. employ molecular motors transport coding noncoding RNAs distal synapses. Intracellular trafficking enables locally regulate protein synthesis synaptic activity. The way get loaded onto transported their target locations, particularly following plasticity, is explored below.

Language: Английский

Citations

0