Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(6), P. 688 - 701

Published: June 1, 2022

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons five AD mouse models vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of pH, multiplex confocal imaging correlative light electron microscopy. Autolysosome acidification declines well before extracellular amyloid deposition, associated with lowered vATPase activity build-up Aβ/APP-βCTF selectively enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This pattern, termed PANTHOS (poisonous anthos (flower)), also present brains. Additional AVs coalesce peri-nuclear networks tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal permeabilization, cathepsin release lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual exhibiting are the principal source senile plaques precursor protein models.

Language: Английский

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Selective motor activation in organelle transport along axons

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(11), P. 699 - 714

Published: May 30, 2022

Language: Английский

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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 926 - 946

Published: Aug. 6, 2024

Language: Английский

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Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration

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

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Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(3)

Published: Feb. 10, 2022

Lysosomes serve as degradation hubs for the turnover of endocytic and autophagic cargos, which is essential neuron function survival. Deficits in lysosome result progressive neurodegeneration most lysosomal storage disorders contribute to pathogenesis aging-related neurodegenerative diseases. Given their size highly polarized morphology, neurons face exceptional challenges maintaining cellular homeostasis regions far removed from cell body where mature lysosomes are enriched. Neurons therefore require coordinated bidirectional intracellular transport sustain efficient clearance capacity distal axonal regions. Emerging lines evidence have started uncover mechanisms signaling pathways regulating endolysosome maturation maintain homeostasis, or "axonostasis," that relevant a range neurologic disorders. In this review, we discuss recent advances how endolysosomal trafficking, distribution, functionality support neuronal health become disrupted several

Language: Английский

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Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca ²⁺ efflux and disrupted by PSEN1 loss of function

Science Advances, Journal Year: 2022, Volume and Issue: 8(17)

Published: April 29, 2022

Dysfunction and mistrafficking of organelles in autophagy- endosomal-lysosomal pathways are implicated neurodegenerative diseases. Here, we reveal selective vulnerability maturing degradative (late endosomes/amphisomes) to disease-relevant local calcium dysregulation. These undergo exclusive retrograde transport axons, with occasional pauses triggered by regulated efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels—an effect greatly exaggerated exogenous agonist synthetic (ML-SA1). Deacidification organelles, as seen after Presenilin (PSEN1) loss function, induced pathological constitutive “inside-out” TRPML1 hyperactivation, slowing their comparably ML-SA1 causing accumulation dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing activity. Blocking JNK activity, or DIC1B serine-80 phosphorylation reversed deficits PSEN1 knockout neurons. Our results, including features demonstrated Alzheimer-mutant knockin mice, define a linking dysfunction lysosomal neuritic dystrophy under conditions.

Language: Английский

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Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr ⁶⁸² -phosphorylated APP βCTF

Science Advances, Journal Year: 2023, Volume and Issue: 9(30)

Published: July 26, 2023

Lysosome dysfunction arises early and propels Alzheimer's disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) disrupt lysosomal vacuolar (H+)-adenosine triphosphatase (v-ATPase) acidification. In human DS fibroblasts, the phosphorylated 682YENPTY internalization motif of APP-βCTF binds selectively within a pocket v-ATPase V0a1 subunit cytoplasmic domain competitively inhibits association V1 subcomplex v-ATPase, thereby reducing activity. Lowering Tyr682 phosphorylation restores lysosome function fibroblasts vivo brains model mice. Notably, lowering below normal constitutive levels boosts assembly activity, suggesting may also be modulated tonically by phospho-APP-βCTF. Elevated two mouse models similarly disrupts function. These findings offer previously unknown insight into pathogenic mechanism underlying faulty lysosomes all forms AD.

Language: Английский

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The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(6)

Published: Feb. 24, 2023

ABSTRACT Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event Alzheimer's disease (AD) pathogenesis. However, mechanisms underlying these abnormalities unclear. The transient receptor potential channel mucolipin 1(TRPML1, also known as MCOLN1), a vital endosomal-lysosomal Ca2+ whose loss of function leads to neurodegeneration, has not been investigated with respect EAL pathogenesis late-onset AD (LOAD). Here, we identify pathological hallmarks TRPML1 dysregulation LOAD neurons, including increased perinuclear clustering and vacuolation endolysosomes. We reveal that induced pluripotent stem cell (iPSC)-derived human cortical neurons expressing APOE ε4, strongest genetic risk factor for LOAD, have significantly diminished TRPML1-induced endolysosomal release. Furthermore, found blocking primary by depleting agonist PI(3,5)P2 via PIKfyve inhibition, recreated multiple features neuropathology evident LOAD. This included content, enlargement endolysosomes, autophagic vesicle accumulation endosomal enlargement. Strikingly, AD-like neuronal defects were rescued reactivation using its synthetic ML-SA1. These findings implicate present therapeutic target.

Language: Английский

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Phosphatidylinositol 3,5-bisphosphate facilitates axonal vesicle transport and presynapse assembly

Science, Journal Year: 2023, Volume and Issue: 382(6667), P. 223 - 230

Published: Oct. 12, 2023

Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the apparatus characterizing neuronal presynapse must form de novo. How components neurotransmission are transported and assembled is poorly understood. Our results show that rare late endosomal signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P

Language: Английский

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Pathobiology of the autophagy-lysosomal pathway in the Huntington’s disease brain

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

Published: May 30, 2024

Abstract Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis Huntington’s disease (HD). Although lowering mHTT by stimulating autophagy has been a possible therapeutic strategy, role competence autophagy-lysosomal pathway (ALP) during HD progression in human remains largely unknown. Here, we used multiplex confocal ultrastructural immunocytochemical analyses ALP functional markers relation aggresome pathology striatum less affected cortex brains staged from HD2 HD4 Vonsattel neuropathological criteria compared controls. Immunolabeling revealed localization HTT/mHTT vesicular compartments labeled autophagy-related adaptor proteins p62/SQSTM1 ubiquitin, cathepsin D (CTSD) as well HTT-positive inclusions. comparatively normal at HD2, neurons later stages exhibited progressive enlargement clustering CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently than cortex. These changes were accompanied rises p62/SQSTM1, particularly their fragments, but not cortex, increases LAMP1 LAMP2 RNA protein. Importantly, no blockage autophagosome formation autophagosome-lysosome fusion was detected, thus pinpointing substrate clearance deficits basis for flux declines. The findings collectively suggest that upregulated lysosomal biogenesis preserved proteolysis maintain early-stage HD, failure advanced contributes HTT build-up potential neurotoxicity. support prospect stimulation applied early stages, when machinery is fully competent, may have benefits patients.

Language: Английский

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