Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Marchesi, Liriopé Toupenet; Leblanc, Marion; Stevanin, Giovanni

doi:10.3390/cells10071678

Cited by 21 publications

(8 citation statements)

References 198 publications

(302 reference statements)

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“…Another aspect of the problem in HSP is the endomembrane and autophagy/lysosomal trafficking (Toupenet Marchesi et al, 2021) which are interconnected with the signaling and receptor recycling/degradation. Cells depend on a highly regulated and dynamic membrane trafficking system for proper intracellular distribution of proteins, lipids, and complex carbohydrates.…”

Section: Pathways Involved In Hsp Pathogenesismentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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Section: Pathways Involved In Hsp Pathogenesismentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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“…, 2022 ), WASHC5 encoding Strumpellin ( Valdmanis et al. , 2007 ), and many others ( Toupenet Marchesi et al. , 2021 ; Garcia-Cazorla et al.…”

Section: Discussionmentioning

confidence: 99%

p97/VCP Promotes the Recycling of Endocytic Cargo

Kawan,

Körner,

Schlosser

et al. 2023

MBoC

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The endocytic pathway is of central importance for eukaryotic cells, as it enables uptake of extracellular materials, membrane protein quality control and recycling, as well as modulation of receptor signaling. While the ATPase p97 (VCP, Cdc48) has been found to be involved in the fusion of early endosomes and endolysosomal degradation, its role in endocytic trafficking is still incompletely characterized. Here, we identify myoferlin (MYOF), a ferlin family member with functions in membrane trafficking and repair, as a hitherto unknown p97 interactor. The interaction of MYOF with p97 depends on the cofactor PLAA previously linked to endosomal sorting. Besides PLAA, shared interactors of p97 and MYOF comprise several proteins involved in endosomal recycling pathways, including Rab11, Rab14 and the transferrin receptor CD71. Accordingly, a fraction of p97 and PLAA localizes to MYOF-, Rab11-, and Rab14-positive endosomal compartments. Pharmacological inhibition of p97 delays transferrin recycling, indicating that p97 promotes not only the lysosomal degradation, but also the recycling of endocytic cargo.

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“…Indeed, it is known from zebrafish and rat cortical neuron studies that, in neurites, Atlastin-1 co-localizes in endosomal structures with BMPR and an inhibitory function is mediated [ 47 , 48 ], implying possible analogies in our SPG3a -mutated lines. Finally, both ATLASTIN 1 and SPASTIN are involved in the formation of endosomes and participate in the delivery to lysosomes or to the autophagic compartments for degradation [ 49 ]. Thereby, a better understanding of the complex interaction between the endocytic and autophagic pathways in the altered, diseased lower MN phenotype could be useful to understand and to possibly develop specific therapeutic interventions for both HSP phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia

Costamagna

Casters

Beltrà

et al. 2022

Cells

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Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP.

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Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cited by 21 publications

References 198 publications

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

p97/VCP Promotes the Recycling of Endocytic Cargo

Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia

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