The role of lysosomal membrane proteins in autophagy and related diseases

Gu, Jing; Pei, Wenjun; Zhang, Yao; Wang, Lizhuo; Gao, Jialin

doi:10.1111/febs.16820

Cited by 8 publications

(2 citation statements)

References 181 publications

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“…In agreement with this observation, the study by Kornhuber and colleagues showed that lysosomal pH is not changed by amitriptyline [95]. Nevertheless, the accumulation of amitriptyline into the lysosomal lumen, as lysosomotropic drug, may affect lysosomal membrane permeability [95] and lysosomal enzymes activity accounting for the delay of autophagic cargo degradation [96,97].…”

Section: Discussionmentioning

confidence: 65%

The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy

Adornetto,

Laganà,

Satriano

et al. 2024

Preprint

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Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and pre-scribed off-label for several neurological conditions like neuropathic pain, migraine and anxiety. Amitriptyline potentiates the monoaminergic transmission by blocking the reuptake of norepi-nephrine and serotonin. However, antidepressants also act on additional targets that contribute to either therapeutic or adverse effects and may suggest new indications for their repurposing. Furthermore, since depression is often a co-morbidity in patients with chronic conditions (i.e. cancer, neurodegenerative diseases) the use of antidepressants interfering with pathways in-volved in cell homeostasis may affect the progression and outcome of these pathologies. Here we investigate the effects of amitriptyline on proliferation and autophagy in human SH-SY5Y neuroblastoma cells. Dose and time-dependent upregulation of the autophagy markers LC3II and autophagy receptor p62, with accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to amitriptyline. Alteration of autophagy was accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5 -/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine suggesting that the amitriptyline’s effects on cell proliferation were not caused by the modulation of autophagy. Our findings demonstrate that amitriptyline acts on pathways that are crucial for cell and tissue homeostasis and pose the basis for further studies on the potential application of these effects and the consequences during long-term antidepressant treatment.

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Section: Discussionmentioning

confidence: 65%

The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy

Adornetto,

Laganà,

Satriano

et al. 2024

Preprint

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“…Where PTC transcripts persist, our data are more consistent with ribosomal readthrough and incorporation of missense substitutions tolerated to differing degrees, than generation of peptides truncated at the PTC. In patient cells, where aberrant protein expression would be low, governed not only by low level RNA transcripts but also by usually rapid endoplasmic reticulum–associated degradation (ERAD) 96 and/or lysosomal 97 degradation, further studies will be required to establish whether and when levels are negligible or not negligible, and whether this differs between missense variants for which cellular processes can adapt to chronic proteotoxic loads, 98 , 99 and PTC variants for which levels are more fluctuant.…”

Section: Discussionmentioning

confidence: 99%

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT

Bernabéu-Herrero,

Patel,

Bielowka

et al. 2024

Blood

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For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we sub-categorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense mediated decay. In three pre-phenotyped patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC patients, PTC-containing RNA transcripts persisted at low levels (8-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni p<0.05 in HHT+/PTC BOECs clustered significantly only to generic protein terms ('isopeptide-bond'/'ubiquitin-like conjugation') and pulse chase experiments detected subtle protein maturation differences, but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of 'invariant' housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor (ATF)4 which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modelled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other "less rare" ENG nonsense variants, but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.

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Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia

Saettini,

Guerra,

Mauri

et al. 2024

J Clin Immunol

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The role of lysosomal membrane proteins in autophagy and related diseases

Cited by 8 publications

References 181 publications

The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy

The Antidepressant Drug Amitriptyline Affects Human SH-SY5Y Neuroblastoma Cell Proliferation and Modulates Autophagy

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT

Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia

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