A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Lupo, Fabio; Tibaldi, Elena; Mattè, Alessandro; Sharma, Alok; Brunati, Anna Maria; Alper, Seth L.; Zancanaro, Carlo; Benati, Donatella; Siciliano, Angela; Bertoldi, Mariarita; Zonta, Francesca; Storch, Alexander; Walker, Ruth H.; Danek, Adrian; Bader, Benedikt; Hermann, Andreas; Franceschi, Lucia De

doi:10.1182/blood-2016-07-727321

Cited by 54 publications

(97 citation statements)

References 67 publications

(113 reference statements)

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“…Impaired autophagy in ChAc erythrocytes leads to the cellular accumulation of multivesicular bodies and membrane remnants [53]. Moreover, the impaired autophagy in chorein deficient reticulocytes appears to delay the clearance of mitochondria and lysosomes [53]. According to observations in erythroid precursors from ChAc patients, chorein deficiency compromises erythropoiesis, increases active Lyn, leads to accumulation of the lysosmal membrane protein LAMP1 and of LAMP1-positive aggregates, and impairs the clearance of lysosomes and mitochondria [53].…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

“…In ChAc erythrocytes active Lyn forms with Heat-Shock-Protein HSP90& 70 high-molecular-weight complexes which protect Lyn from proteasomal degradation [53]. The complexes bind to Ulk1 and Atg7 [53]. The association of chorein with Atg7 is compromised in ChAc erythrocytes.…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

“…Autophagy in turn strongly impacts on apoptosis [50-52]. In ChAc eythrocytes autophagy is decreased [53] and cytoplasmic levels of active Lyn and of autophagy-related proteins Ulk1 and Atg7 are enhanced [53]. In ChAc erythrocytes active Lyn forms with Heat-Shock-Protein HSP90& 70 high-molecular-weight complexes which protect Lyn from proteasomal degradation [53].…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

“…The association of chorein with Atg7 is compromised in ChAc erythrocytes. Impaired autophagy in ChAc erythrocytes leads to the cellular accumulation of multivesicular bodies and membrane remnants [53]. Moreover, the impaired autophagy in chorein deficient reticulocytes appears to delay the clearance of mitochondria and lysosomes [53].…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

“…Moreover, the impaired autophagy in chorein deficient reticulocytes appears to delay the clearance of mitochondria and lysosomes [53]. According to observations in erythroid precursors from ChAc patients, chorein deficiency compromises erythropoiesis, increases active Lyn, leads to accumulation of the lysosmal membrane protein LAMP1 and of LAMP1-positive aggregates, and impairs the clearance of lysosomes and mitochondria [53]. Thus, chorein deficiency leads to accumulation of active Lyn, impairs autophagy, and thus compromises vesicle trafficking in erythroid maturation [53].…”

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

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Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

et al. 2017

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Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca²⁺-channel accomplishing store operated Ca²⁺-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.

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Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

Section: Autophagy and Cell Survivalmentioning

confidence: 99%

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Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

et al. 2017

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PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Werning

Müllner

Mlynek

et al. 2020

Ann Clin Transl Neurol

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Objective Pantothenate kinase 2‐associated neurodegeneration (PKAN) is a rare neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene. PKAN is associated with iron deposition in the basal ganglia and, occasionally, with the occurrence of misshaped erythrocytes (acanthocytes). The aim of this study was to assess residual activity of PANK2 in erythrocytes of PKAN patients and to correlate these data with the type of PANK2 mutations and the progression of neurodegeneration. Methods Residual PANK2 activities in erythrocytes of 14 PKAN patients and 14 related carriers were assessed by a radiometric assay. Clinical data on neurodegeneration included the Barry–Albright Dystonia Scale (BAD‐Scale) besides further general patient features. A molecular visualization and analysis program was used to rationalize the influence of the PKAN causing mutations on a molecular level. Results Erythrocytes of PKAN patients had markedly reduced or no PANK2 activity. However, patients with at least one allele of the c.1583C > T (T528M) or the c.833G > T (R278L) variant exhibited 12–56% of residual PANK2 activity. In line, molecular modeling indicated only minor effects on enzyme structure for these point mutations. On average, these patients with c.1583C > T or c.833G > T variant had lower BAD scores corresponding to lower symptom severity than patients with other PANK2 point mutations. Interpretation Residual erythrocyte PANK2 activity could be a predictor for the progression of neurodegeneration in PKAN patients. Erythrocytes are an interesting patient‐derived cell system with still underestimated diagnostic potential.

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Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

et al. 2018

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The signaling cascade induced by the interaction of erythropoietin (EPO) with its receptor (EPO‐R) is a key event of erythropoiesis. We present here data indicating that Fyn, a Src‐family‐kinase, participates in the EPO signaling‐pathway, since Fyn−/− mice exhibit reduced Tyr‐phosphorylation of EPO‐R and decreased STAT5‐activity. The importance of Fyn in erythropoiesis is also supported by the blunted responsiveness of Fyn−/− mice to stress erythropoiesis. Fyn−/− mouse erythroblasts adapt to reactive oxygen species (ROS) by activating the redox‐related‐transcription‐factor Nrf2. However, since Fyn is a physiologic repressor of Nrf2, absence of Fyn resulted in persistent‐activation of Nrf2 and accumulation of nonfunctional proteins. ROS‐induced over‐activation of Jak2‐Akt‐mTOR‐pathway and repression of autophagy with perturbation of lysosomal‐clearance were also noted. Treatment with Rapamycin, a mTOR‐inhibitor and autophagy activator, ameliorates Fyn−/− mouse baseline erythropoiesis and erythropoietic response to oxidative‐stress. These findings identify a novel multimodal action of Fyn in the regulation of normal and stress erythropoiesis.

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A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Cited by 54 publications

References 67 publications

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

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