“Neuroacanthocytosis” – Overdue for a Taxonomic Update

Walker, Ruth H.; Danek, Adrian

doi:10.5334/tohm.583

Cited by 33 publications

(36 citation statements)

References 36 publications

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“…McLeod syndrome, which more closely resembles chorea-acanthocytosis [ 108 ] is due to mutations of the XK gene [ 109 ] which encodes a protein enriched in the erythrocyte membrane (X-Linked Kx Blood Group) [ 60 ]. As discussed above, the predicted function of VPS13 proteins in phosholipid transport is thought to require the action of lipid scramblases to allow for equilibration of phospholipids between the bilayers of donor and acceptor membranes.…”

Section: Disease Mechanismsmentioning

confidence: 99%

Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport

Leonzino

Reinisch

Camilli

2021

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The occurrence of protein mediated lipid transfer between intracellular membranes has been known since the late 1960's. Since these early discoveries, numerous proteins responsible for such transport, which often act at membrane contact sites, have been identified. Typically, they comprise a lipid harboring module thought to shuttle back and forth between the two adjacent bilayers. Recently, however, studies of the chorein domain protein family, which includes VPS13 and ATG2, has led to the identification of a novel mechanism of lipid transport between organelles in eukaryotic cells mediated by a rod-like protein bridge with a hydrophobic groove through which lipids can slide. This mechanism is ideally suited for bulk transport of bilayer lipids to promote membrane growth. Here we describe how studies of VPS13 led to the discovery of this new mechanism, summarize properties and known roles of VPS13 proteins, and discuss how their dysfunction may lead to disease.

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Section: Disease Mechanismsmentioning

confidence: 99%

Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport

Leonzino

Reinisch

Camilli

2021

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Chorea-acanthocytosis (ChAc) is a rare neurodegenerative disease of the early adulthood which is characterized by a large spectrum of neurological symptoms and the presence of acanthocytes [ 1 , 2 , 3 , 4 ]. The autosomal-recessive condition is caused by mutations in the VPS13A gene leading to loss of function of the respective encoded protein “chorein” [ 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease

Peikert

Glaß

Federti

et al. 2021

JPM

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Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

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“…Human VPS13A protein is of great interest because loss-of-function mutations in its coding gene lead to Chorea-acanthocytosis (ChAc; MIM 200150), a very rare and complex autosomal recessive adult-onset neurodegenerative disorder [ 1 , 2 ]. In accordance with this etiology, ChAc has recently proposed to be renamed as VPS13A disease [ 3 ]. The main neuropathologic feature in VPS13A disease is a selective degeneration of the caudate and putamen nuclei [ 4 , 5 , 6 ], due to massive cell death of medium spiny neurons (MSNs) and striatal interneurons [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Spatiotemporal Distribution of VPS13A in the Mouse Brain

García-García

Chaparro-Cabanillas

Coll-Manzano

et al. 2021

IJMS

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Loss-of-function mutations in the human vacuolar protein sorting the 13 homolog A (VPS13A) gene cause Chorea-acanthocytosis (ChAc), with selective degeneration of the striatum as the main neuropathologic feature. Very little is known about the VPS13A expression in the brain. The main objective of this work was to assess, for the first time, the spatiotemporal distribution of VPS13A in the mouse brain. We found VPS13A expression present in neurons already in the embryonic stage, with stable levels until adulthood. VPS13A mRNA and protein distributions were similar in the adult mouse brain. We found a widespread VPS13A distribution, with the strongest expression profiles in the pons, hippocampus, and cerebellum. Interestingly, expression was weak in the basal ganglia. VPS13A staining was positive in glutamatergic, GABAergic, and cholinergic neurons, but rarely in glial cells. At the cellular level, VPS13A was mainly located in the soma and neurites, co-localizing with both the endoplasmic reticulum and mitochondria. However, it was not enriched in dendritic spines or the synaptosomal fraction of cortical neurons. In vivo pharmacological modulation of the glutamatergic, dopaminergic or cholinergic systems did not modulate VPS13A concentration in the hippocampus, cerebral cortex, or striatum. These results indicate that VPS13A has remarkable stability in neuronal cells. Understanding the distinct expression pattern of VPS13A can provide relevant information to unravel pathophysiological hallmarks of ChAc.

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“Neuroacanthocytosis” – Overdue for a Taxonomic Update

Cited by 33 publications

References 36 publications

Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport

Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease

Unraveling the Spatiotemporal Distribution of VPS13A in the Mouse Brain

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