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Results for “Protein Aggregation, Pathological”

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PubMed2003

Immunophilins in nervous system degeneration and regeneration.

Immunophilins are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their non- immunosuppressive analogs, which are collectively referred to as "immunophilin ligands" (IPL). Cyclosporin A binds to a class of IP called cyclophilins, whereas the receptors for FK506 and rapamycin belong to the family of FK506- binding proteins (FKBP). The latter are designated according to their molecular weight: FKBP12, 25, 52 etc. FKBP levels in the rat brain are up to 50 times higher than in the immune system. FKBP12 is associated with IP3 and ryanodine receptors present on the endoplasmic reticulum and plays a role in stabilizing calcium release. It has also been proposed to be a modulator of the TGFbeta receptor activity. Crush injury of facial or sciatic nerves in rat leads to markedly increased FKBP12 levels in the respective nerve nuclei and this increase is related to nerve regeneration. Cyclophilin A protects cells from death following expression of mutant Cu/ Zn superoxide dismutase, which is associated with familial amyotrophic lateral sclerosis. Our recent studies show that FKBP12 and FKBP52 are expressed in the human nervous system, especially in the substantia nigra- deep gray matter axis. In neurodegenerative diseases, FKBP12 levels increase in neurons situated in areas of pathology. This IP colocalizes with synaptophysin and alpha- synuclein, suggesting that it may become a novel marker of pathology. Immunophilins participate in axonal transport, synaptic vesicle assembly and may play a role in neuroprotection against abnormal protein aggregation, suggesting a potential avenue of therapeutic interventions.

Animals↗

PubMed1991

Spindle cell stromal tumors of gastrointestinal tract: a histological and immunohistochemical study.

Twenty-one consecutive cases of gastrointestinal spindle cell stromal tumors (SCSTs) were studied histologically and immunohistochemically. They consisted of 18 smooth muscle tumors, 2 neurilemmomas (schwannomas), and 1 unclassified malignant tumor designated as stromal sarcoma. Slender, spindle and wavy nuclei with palisading associated with peripheral tumor aggregation of lymphocytes are the pathological hallmarks of neurilemmoma. With peroxidase-antiperoxidase method, antibodies to Glial Fibrillary Acidic Protein (GFAP), Leu-7, S-100, desmin and HHF35 were applied. Antibodies to Leu-7 and GFAP could only be demonstrated in neurilemmomas (2 cases). Antibody to S-100 was observed strongly in 2 neurilemmomas and 1 stromal sarcoma, and focally in a leiomyoma, while the other SCSTs were negative. One neurilemmoma disclosed focal positivity of desmin. Six of 10 leiomyomas revealed varied degrees of positive staining of desmin and HHF35. One epithelioid leiomyoma, two leiomyosarcomas and five smooth muscle tumors of undetermined malignant potential (STUMP) disclosed no immunoreactivity. The study suggests that panel of immunostaining should be applied. Coexpression of GFAP, Leu-7 and S-100 as well as negative staining of HHF35 is characteristic of neurilemmoma. On the contrary, coexpression of desmin and HHF35 while negative for GFAP, S-100 and Leu-7 are suggestive of smooth muscle tumor. In poorly differentiated SCST, histological features and immunostains are always disappointing. Diagnosis of those tumors as stromal tumor is more appropriate or electron microscopic observation should be included for accurate classification.

Adult↗

PubMed1996

In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta.

The two pathological lesions found in the brains of Alzheimer's disease patients, neurofibrillary tangles and neuritic plaques, are likely to be formed through a common pathway. Neurofibrillary tangles are intracellular aggregates of paired helical filaments, the main component of which is hyperphosphorylated forms of the microtubule-associated protein tau. Extracellular neuritic plaques and diffuse and vascular amyloid deposits are aggregates of beta-amyloid protein, a 4-kDa protein derived from the amyloid precursor protein (APP). Using conditions in vitro under which two proline-directed protein kinases, glycogen synthase kinase-3beta (GSK-3beta) and mitogen-activated protein kinase (MAPK), were able to hyperphosphorylate tau, GSK-3beta but not MAPK phosphorylated recombinant APPcyt. The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). This site was confirmed by endoproteinase Glu-C digestion of APPcyt and peptide sequencing. The ability of GSK-3beta to phosphorylate APPcyt and tau provides a putative link between the two lesions and indicates a critical role of GSK-3beta in the pathogenesis of Alzheimer's disease.

Amino Acid Sequence↗

PubMed2002

Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment.

Huntington's disease is caused by the expansion of CAG repeats coding for a polyglutamine tract in the huntingtin protein. The major pathological feature found in Huntington's disease neurons is the presence of detergent-insoluble ubiquitinated inclusion bodies composed of the huntingtin protein. However, the mechanisms that underlie inclusion body formation, and the precise relationship between inclusion bodies and events that initiate toxicity, remain unclear. Here, we analyzed the effects of drugs or genetic mutations that disrupt the microtubule cytoskeleton in a Saccharomyces cerevisiae model of the aggregation of an amino-terminal polyglutamine-containing fragment of huntingtin exon 1 (HtEx1). Treatment of yeast with drugs that disrupt microtubules resulted in less than 2% of the detergent-insoluble HtEx1 observed in mock-treated cells and prevented the formation of large juxtanuclear inclusion bodies. Disruption of microtubules also unmasked a potent glutamine length-dependent toxicity of HtEx1 under conditions where HtEx1 exists in an entirely detergent-soluble nonaggregated form. Results from the yeast model paralleled those from neuronal pheochromocytoma cells, where disruption of microtubules eliminated the formation of juxtanuclear and intranuclear inclusion bodies by HtEx1. Our results suggest that active transport along microtubules may be required for inclusion body formation by HtEx1 and that inclusion body formation may have evolved as a cellular mechanism to promote the sequestration or clearance of soluble species of HtEx1 that are otherwise toxic to cells.

Cytoskeleton↗

PubMed2001

Alpha synuclein aggregation: is it the toxic gain of function responsible for neurodegeneration in Parkinson's disease?

Protein aggregation appears to be the common denominator in a series of distinct neurodegenerative diseases yet its role in the associated neuronal pathology in these various conditions remains elusive. In Parkinson's disease, localization of alpha synuclein aggregates within intracellular Lewy body occlusions represent a major hallmark of this disorder and suggest that such aggregation may play a causative role in the resulting dopaminergic cell loss. In this Viewpoint article, recent data is reviewed related to how alpha synuclein aggregation may occur, what cellular events might be responsible, and how this may interfere with normal cellular function(s). It appears likely that while aggregation of alpha synuclein may interfere with its normal function in the cell, this is not the primary cause of the related neurodegeneration.

Animals↗

PubMed2006

Acidic pH-induced conformational changes in amyloidogenic mutant transthyretin.

Several proteins, including transthyretin (TTR), can generate in tissues extracellular insoluble aggregates, in the form of fibrils, that are associated with pathological states known as amyloidoses. To date, more than 80 different TTR point mutations have been associated with hereditary amyloidosis in humans. In vitro, the formation of amyloid fibrils by human TTR is known to be triggered by acidic pH. We show here that, in vitro, the natural amyloidogenic I84S and the non-natural I84A TTR mutant forms exhibit a propensity to produce fibrils in an acidic medium significantly higher than that of wild-type TTR. The two mutant forms have been crystallized at both neutral and acidic pH. Their neutral pH crystal structures are very similar to that of wild-type TTR, consistent with previous evidence indicating that only minor structural changes are induced by amyloidogenic mutations. On the contrary, their crystal structures at moderately low pH (4.6) show significant conformational differences as compared to their neutral pH structures. Remarkably, such changes are not induced in wild-type TTR crystallized at low pH. The most relevant consist of the unwinding of the TTR short alpha-helix and of the change in conformation of the loop connecting the alpha-helix to beta-strand F. Only one monomer of the crystallographic dimer is affected, causing a disruption of the tetrameric symmetry. This asymmetry and a possible destabilization of the tetrameric quaternary structure of TTR may be responsible for the amyloidogenic potential of the two TTR mutant forms at low pH.

Alanine↗

PubMed2006

Autophagic stress in neuronal injury and disease.

Autophagy is the regulated process by which cytoplasmic organelles and long-lived proteins are delivered for lysosomal degradation. Increased numbers of autophagosomes and autolysosomes often represent prominent ultrastructural features of degenerating or dying neurons. This morphology is characteristic not only of neurons undergoing pathologic degeneration, but also during developmental programmed cell death of some neuronal populations. In recent years, a growing number of reports highlight potentially important roles for autophagy-related processes in relation to protein aggregation, regulated cell death pathways, and neurodegeneration. While starvation-induced autophagy involves nonselective bulk degradation of cytoplasm, mechanisms that regulate selective targeting of damaged organelles form an emerging area. As the study of autophagy evolves from physiologic homeostasis to pathologic situations, consideration of terminology and definitions becomes important. Increased autophagic vacuoles do not necessarily correlate with increased autophagic activity or flux. Instead, the striking accumulation of autophagic vacuoles in dying or degenerating neurons likely reflects an imbalance between the rates of autophagic sequestration and completion of the degradative process. In other words, these cells can be thought of as undergoing "autophagic stress." The concept of autophagic stress may reconcile apparently conflicting roles of autophagy-related processes in adaptive, homeostatic responses and in pathways of neurodegeneration and cell death.

Animals↗

PubMed2004

Ionic regulation of proteins.

Ion binding modulates the structural and the functional properties of several proteins. The molecular bases of such interactions depend on the charge density of ions, in turn influencing their ability to bind water molecules. The broad range of proteins submitted to ionic control, makes it interesting a general evaluation of the role played by ions in the homeostasis of intra and extracellular compartments and in a number of physio-pathological conditions, with special attention to the coagulation cascade and cryoglobulin aggregation.

Anions↗

PubMed2003

Parkinsonism plus syndrome--a review.

Parkinsonism plus syndrome is a group of heterogeneous degenerative neurological disorders, which differ from the classical idiopathic Parkinson's disease in certain associated clinical features, poor response to levodopa, distinctive pathological characteristics and poor prognosis. Associated clinical features include symmetrical onset, infrequent or atypical tremor, prominent rigidity in axial musculature, bradykinesia, early postural instability, supranuclear gaze palsy, early autonomic failure, pyramidal affection, cerebellar involvement, alien limb phenomenon, apraxia and significant early cognitive dysfunction in some cases. Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and dementia with Lewy body disease (DLB) are commoner disorders. Less frequent disorders are cortico-basal ganglionic degeneration (CBGD), frontotemporal dementia with chromosome 17 (FTDP-17), Pick's disease, parkinsonian-dementia complex of Guam, Pallidonigral degeneration, Wilson's disease and a rigid variant of Huntington's disease. During the last 3 decades, major progress has been made in understanding PSP, CBGD and FTDP-17, which are tau disorders. MSA and DLB together with idiopathic Parkinson's disease are called alpha-synucleinopathies. Recent studies show that the diagnosis of these Parkinsonism plus syndromes improves when strict diagnostic criteria are used. However, unusual presentations may pose a diagnostic challenge. The shortcomings of the current studies demand the need for further research to identify biologic markers that may allow earlier diagnosis, and understanding of the factors leading to alpha-synuclein or tau aggregation. Identification of therapeutic strategies that may prevent the aggregation of these proteins and rescue dysfunctional cells has been stressed. This review focuses on the advances in the clinical, neuroimaging, pathologic, genetic and management aspects of these disorders.

Humans↗

PubMed2005

Novel heparan sulphate analogues: inhibition of beta-secretase cleavage of amyloid precursor protein.

The role of HS (heparan sulphate) in the pathology of AD (Alzheimer's disease) is multifaceted. HS and other glycosaminoglycans have been widely reported to be associated with neuritic plaques. HS has also been shown to promote the aggregation of Abeta (amyloid beta-peptide), the proteinaceous component of neuritic plaques. Recently, we described a novel and contrasting role for HS in the pathology of AD: HS can inhibit the formation of Abeta, by directly interacting with the protease BACE1 (beta-site amyloid precursor protein cleaving enzyme 1; beta-secretase 1), that cleaves the amyloid precursor protein and is the rate limiting step in the generation of Abeta. Here, we review the current roles of HS and the potential for HS-derivatives in the treatment of AD.

Alzheimer Disease↗

PubMed2005

The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways.

Alpha-synuclein is a major component of Lewy bodies, the pathological hallmark of Parkinson disease, dementia with Lewy bodies, and related disorders. Misfolding and aggregation of alpha-synuclein is thought to be a critical cofactor in the pathogenesis of certain neurodegenerative diseases. In the current study, we investigate the role of the carboxyl terminus of Hsp70-interacting protein (CHIP) in alpha-synuclein aggregation. We demonstrate that CHIP is a component of Lewy bodies in the human brain, where it colocalizes with alpha-synuclein and Hsp70. In a cell culture model, endogenous CHIP colocalizes with alpha-synuclein and Hsp70 in intracellular inclusions, and overexpression of CHIP inhibits alpha-synuclein inclusion formation and reduces alpha-synuclein protein levels. We demonstrate that CHIP can mediate alpha-synuclein degradation by two discrete mechanisms that can be dissected using deletion mutants; the tetratricopeptide repeat domain is critical for proteasomal degradation, whereas the U-box domain is sufficient to direct alpha-synuclein toward the lysosomal degradation pathway. Furthermore, alpha-synuclein, synphilin-1, and Hsp70 all coimmunoprecipitate with CHIP, raising the possibility of a direct alpha-synuclein-CHIP interaction. The fact that the tetratricopeptide repeat domain is required for the effects of CHIP on alpha-synuclein inclusion morphology, number of inclusions, and proteasomal degradation as well as the direct interaction of CHIP with Hsp70 implicates a cooperation of CHIP and Hsp70 in these processes. Taken together, these data suggest that CHIP acts a molecular switch between proteasomal and lysosomal degradation pathways.

Cell Line, Tumor↗

PubMed1995

Protein tyrosine phosphorylation in human platelets during shear stress-induced platelet aggregation (SIPA) is regulated by glycoprotein (GP) Ib/IX as well as GP IIb/IIIa and requires intact cytoskeleton and endogenous ADP.

Shear stress-induced platelet aggregation (SIPA) may be essential in thrombus formation in pathologically stenotic arteries. Intracellular events during SIPA are, however, poorly understood. Washed platelets were exposed to shear stress (108 dyne/cm2) in the presence of von Willebrand factor (vWf, 10 micrograms/ml) and 1 mM CaCl2 for various time intervals, and then lyzed in SDS. Platelet proteins were separated by 10% SDS-PAGE and tyrosine phosphorylated proteins were detected by immunoblotting with an anti-phosphotyrosine monoclonal antibody. Increased tyrosine phosphorylation of proteins of 130, 100, 85, 74, 70, 64, 58, and 40 kDa was observed within 30 s after the beginning of exposure of platelets to high shear force and the degree of tyrosine phosphorylation continued to increase up to approximately 2 min after the exposure. A monoclonal antibody (MoAb) against vWf-binding domain of glycoprotein (GP) Ib alpha (GUR83-35), anti-vWf MoAb that inhibits binding of vWf to GPIb alpha (NMC-4), or a MoAb against GP IIb/IIIa complex (AP-2) inhibited SIPA as well as tyrosine phosphorylation of these proteins. Apyrase (an ADP scavenger, 2 U/ml), EDTA (5 mM), or RGDS peptide (200 micrograms/ml) also had inhibitory effects on both SIPA and tyrosine phosphorylation. However, Cytochalasin D (2 microM) or staurosporin (1 microM) did not affect SIPA, while they inhibited SIPA-associated tyrosine phosphorylation of those proteins. SIPA-associated tyrosine phosphorylation is a novel post-aggregatory pathway in signal transduction, which is dependent on the binding of vWf to GP Ib/IX and GP IIb/IIIa, endogenous ADP, and intact cytoskeleton.

Adenosine Diphosphate↗

PubMed2005

Progressive and selective striatal degeneration in primary neuronal cultures using lentiviral vector coding for a mutant huntingtin fragment.

A lentiviral vector expressing a mutant huntingtin protein (htt171-82Q) was used to generate a chronic model of Huntington's disease (HD) in rat primary striatal cultures. In this model, the majority of neurons expressed the transgene so that Western blot analysis and flow cytometry measurement could complement immunohistological evaluation. Mutant huntingtin produced a slowly progressing pathology characterized after 1 month by the appearance of neuritic aggregates followed by intranuclear inclusions, morphological anomalies of neurites, loss of neurofilament 160, increased expression in stress response protein Hsp70, and later loss of neuronal markers such as NeuN and MAP-2. At 2 months post-infection, a significant increase in TUNEL-positive cells confirmed actual striatal cell loss. Interestingly, cortical cultures infected with the same vector showed no sign of neuronal dysfunction despite accumulation of numerous inclusions. We finally examined whether the trophic factors CNTF and BDNF that were found neuroprotective in acute HD models could prevent striatal degeneration in a chronic model. Results demonstrated that both agents were neuroprotective without modifying inclusion formation. The present study demonstrates that viral vectors coding for mutant htt provides an advantageous system for histological and biochemical analysis of HD pathogenesis in primary striatal cultures.

Animals↗

PubMed2000

A nonfibrillar form of the fusogenic prion protein fragment [118-135] induces apoptotic cell death in rat cortical neurons.

Neuronal loss is a salient feature of prion diseases. However, its cause and mechanism, particularly its relationship with the accumulation and precipitation of the pathogenic, protease-resistant isoform PrP(Sc) of the cellular prion protein PrP(C), are still an enigma. Several studies suggest that neuronal loss could occur through a process of programmed cell death, which is consistent with the lack of inflammation in these conditions. By analogy with the pathological events occurring during the development of Alzheimer's disease, controversies still exist regarding the relationship between amyloidogenesis, prion aggregation, and neuronal loss. We recently demonstrated that a prion protein fragment (118-135) displayed membrane-destabilizing properties and was able to induce, in a nonfibrillar form, the fusion of unilamellar liposomes. To unravel the mechanism of prion protein neurotoxicity, we characterize the effects of the human Pr[118-135] peptide on rat cortical neurons. We demonstrate that low concentrations of the Pr[118-135] peptide, in a nonfibrillar form, induce a time- and dose- dependent apoptotic cell death, including caspase activation, DNA condensation, and fragmentation. This toxicity might involve oxidative stress, because antioxidant molecules, such as probucol and propyl gallate, protect neurons against prion peptide toxicity. By contrast, a nonfusogenic variant Pr[118-135, 0 degrees ] peptide, which displays the same amino acid composition but several amino acid permutations, is not toxic to cortical neurons, which emphasizes the critical role of the fusogenic properties of the prion peptide in its neurotoxicity. Taken together, our results suggest that the interaction between the Pr[118-135] peptide and the plasma membrane of neurons might represent an early event in a cascade leading to neurodegeneration.

Amino Acid Chloromethyl Ketones↗

PubMed2005

Promotion of oxidative lipid membrane damage by amyloid beta proteins.

Senile plaques in the cerebral parenchyma are a pathognomonic feature of Alzheimer's disease (AD) and are mainly composed of aggregated fibrillar amyloid beta (Abeta) proteins. The plaques are associated with neuronal degeneration, lipid membrane abnormalities, and chemical evidence of oxidative stress. The view that Abeta proteins cause these pathological changes has been challenged by suggestions that they have a protective function or that they are merely byproducts of the pathological process. This investigation was conducted to determine whether Abeta proteins promote or inhibit oxidative damage to lipid membranes. Using a mass spectrometric assay of oxidative lipid damage, the 42-residue form of Abeta (Abeta42) was found to accelerate the oxidative lipid damage caused by physiological concentrations of ascorbate and submicromolar concentrations of copper(II) ion. Under these conditions, Abeta42 was aggregated, but nonfibrillar. Ascorbate and copper produced H(2)O(2), but Abeta42 reduced H(2)O(2) concentrations, and its ability to accelerate oxidative damage was not affected by catalase. Lipids could be oxidized by H(2)O(2) and copper(II) in the absence of ascorbate, but only at significantly higher concentrations, and Abeta42 inhibited this reaction. These results indicate that the ability of Abeta42 to promote oxidative damage is more potent and more likely to be manifest in vivo than its ability to inhibit oxidative damage. In conjunction with prior results demonstrating that oxidatively damaged membranes cause Abeta42 to misfold and form fibrils, these results suggest a specific chemical mechanism linking Abeta42-promoted oxidative lipid damage to amyloid fibril formation.

Amyloid beta-Peptides↗

PubMed1997

Role of serotonin in nephrotoxic serum nephritis in WKY rats.

Our objective was to determine whether serotonin is involved in inducing nephrotoxic serum nephritis in WKY rats. After injection of antiglomerular basement membrane antiserum, urinary protein excretion was significantly decreased in rats treated with the serotonin receptor antagonist, MCI-9042, and in rats treated with p-chlorophenylalanine. Similarly, severe necrotizing lesions and crescent formation were inhibited in a dose-dependent manner by treatment with MCI-9042 and p-chlorophenylalanine. The number of intraglomerular ED-1-positive cells was increased on day 3 and thereafter in the placebo group. A significant increase in the number of crescent lesions was observed in the placebo group on day 7 and thereafter. Neither adenosine diphosphate- nor collagen-induced platelet aggregations were inhibited in platelet-rich plasma from rats treated with MCI-9042. No significant differences were observed in the production of circulating antibody and antibody deposition in rat glomeruli among the study groups. These results indicate that pathologic changes and urinary protein excretion are closely related to the presence of serotonin in nephrotoxic serum nephritis of WKY rats. Thus serotonin may play a key role in the glomerular injury in this model. Studies on the mode of action of MCI-9042 on platelet aggregation in vivo indicate that the antiplatelet effect of this drug did not contribute to the inhibition of renal injury in this experimental model. This study suggests that serotonin participates in macrophage-mediated immune injury in nephrotoxic serum nephritis of WKY rats.

Animals↗

PubMed2000

Aggregation and fibrillization of the recombinant human prion protein huPrP90-231.

According to the "protein-only" hypothesis, the critical step in the pathogenesis of prion diseases is the conformational transition between the normal (PrP(C)) and pathological (PrP(Sc)) isoforms of prion protein. To gain insight into the mechanism of this transition, we have characterized the biophysical properties of the recombinant protein corresponding to residues 90-231 of the human prion protein (huPrP90-231). Incubation of the protein under acidic conditions (pH 3.6-5) in the presence of 1 M guanidine-HCl resulted in a time-dependent transition from an alpha-helical conformation to a beta-sheet structure and oligomerization of huPrP90-231 into large molecular weight aggregates. No stable monomeric beta-sheet-rich folding intermediate of the protein could be detected in the present experiments. Kinetic analysis of the data indicates that the formation of beta-sheet structure and protein oligomerization likely occur concomitantly. The beta-sheet-rich oligomers were characterized by a markedly increased resistance to proteinase K digestion and a fibrillar morphology (i.e., they had the essential physicochemical properties of PrP(Sc)). Contrary to previous suggestions, the conversion of the recombinant prion protein into a PrP(Sc)-like form could be accomplished under nonreducing conditions, without the need to disrupt the disulfide bond. Experiments in urea indicate that, in addition to acidic pH, another critical factor controlling the transition of huPrP90-231 to an oligomeric beta-sheet structure is the presence of salt.

Chromatography, Gel↗

PubMed2004

Alexander disease: putative mechanisms of an astrocytic encephalopathy.

Alexander disease (AXD) is the first primary astrocytic disorder. This encephalopathy is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, encoding the main intermediate filament of astrocyte. Pathologically, this neurodegenerative disease is characterised by dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities. More than 20 GFAP mutations have been reported. Many of them cluster in highly conserved regions between several intermediate filaments. Contrary to other intermediate filament-related diseases, AXD seems to be the consequence of a toxic gain of function induced by aggregates. This is supported by the phenotype of mice overexpressing human GFAP. Nevertheless, GFAP null mice display myelin abnormalities and blood-brain barrier dysfunction that are present in AXD. Given the pivotal role of astrocytes in brain physiology, there are many possibilities for astrocytes to dysfunction and to impair the functions of other cells. Physiopathological hypotheses are discussed in the frame of AXD.

Alexander Disease↗