Asta Literature Retrieval: Pathophysiology and clinical mechanisms of pantothenate kinase-associated neurodegeneration. Core disease mechanisms,...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models

• Authors: D. Elbaum, M. Beconi, E. Monteagudo, A. Di Marco, M. Quinton et al.
• Year: 2018
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/224c4a95ba72dc8d7dfd68b29381e52cfe2a36d8
• DOI: 10.1371/journal.pone.0192028
• PMID: 29522513
• PMCID: 5844530
• Citations: 24
• Influential citations: 2
• Summary: Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model, which supports the hypothesis that fosmetPantOTenate acts to replace reduced phosphopantothenic acid in pantOThenate Kinase 2-deficient tissues.
• Evidence snippets:
• Snippet 1 (score: 0.618) > Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive neurodegenerative disease [1][2][3] caused by a mutation in the pantothenate kinase-2 (PANK2) gene on chromosome 20p13. More than 100 mutations have been published [4], including missense, nonsense, splice-site, and frameshift mutations [5]. PKAN manifests as a range of signs of parkinsonism, dystonia, and other systemic features. The clinical presentation, age of onset, and rate of progression are highly variable, even among siblings and case clusters with identical mutations [5][6][7][8][9], leading to a poor understanding of the genotype/phenotype relationship [10]. > In PKAN, the mutation in the PANK2 gene, encoding the mitochondrial form of pantothenate kinase (PanK), causes a reduction in the activity of the PanK2 enzyme, which converts pantothenate (PA, vitamin B5) to phosphopantothenate (PPA), in the biosynthetic pathway to coenzyme A (CoA) [11]. It has been postulated that the defective PanK2 enzyme, localized primarily in mitochondria [1], has decreased ability to phosphorylate pantothenate, leading to decreased concentrations of CoA in vulnerable tissues, including brain. CoA and its acetylated metabolite, acetyl-CoA, are key factors in several cellular processes, including energy metabolism, autophagy, and mitosis, acting as a central metabolic intermediate and as signal transducers in anabolic and catabolic reactions [12]. > Currently, there is no disease-modifying or specific therapy for patients with PKAN. Fosmetpantotenate (RE-024, Fig 1) is under development as a PPA replacement therapy to treat patients with PKAN.

[2] Pathology and treatment methods in pantothenate kinase-associated neurodegeneration

• Authors: Robert Kwinta, Katarzyna Kopcik, Agnieszka Koberling
• Year: 2024
• Venue: Advances in Psychiatry and Neurology
• URL: https://www.semanticscholar.org/paper/192fd1d78eaf44b99b06dfa099b7c7a758652f32
• DOI: 10.5114/ppn.2024.141713
• PMID: 39678459
• PMCID: 11635428
• Citations: 3
• Summary: There are many studies on the pathophysiology and treatment methods for PKAN patients, but the results are still limited and the future of PKAN treatment will be characterized by personalized treatment that is based on the patient’s genetic and environmental factors.
• Evidence snippets:
• Snippet 1 (score: 0.575) > Purpose The purpose of this review is to present current scientific reports on the pathophysiology, diagnosis and treatment of pantothenate kinase-associated neurodegeneration (PKAN). Views The condition is caused by a mutation in the PANK2 gene, which results in iron accumulation in the brain and changes in the functioning of biochemical pathways dependent on coenzyme A. There are two clinical types of PKAN, which differ in the time of onset of symptoms and speed of disease progression. Imaging studies, specifically magnetic resonance (MR), and genetic testing are commonly used in the diagnosis process. The characteristic radiological image seen in T2-MR images is the “eye of the tiger”. Patients with PKAN can only receive treatment for symptoms because there are no effective treatment methods available. Pharmacological methods include symptomatic medications, such as pregabalin, gabapentin, or botulinum toxin, and disease-modifying agents, such as iron chelators. Surgical procedures or deep brain stimulation as alternative methods can also be considered. The review presents data from studies published between 2017 and 2024. Conclusions There are many studies on the pathophysiology and treatment methods for PKAN patients, but the results are still limited. The future of PKAN treatment will be characterized by personalized treatment that is based on the patient’s genetic and environmental factors. Further investigation of these is necessary.
• Snippet 2 (score: 0.448) > Pathology and treatment methods in pantothenate kinase-associated neurodegeneration

[3] Precision medicine in pantothenate kinase-associated neurodegeneration

• Authors: Mónica Álvarez-Córdoba, Marina Villanueva-Paz, Irene Villalón-García, Suleva Povea-Cabello, J. M. Suárez-Rivero et al.
• Year: 2019
• Venue: Neural Regeneration Research
• URL: https://www.semanticscholar.org/paper/104071a7056b54028f1359590853112a99feaad7
• DOI: 10.4103/1673-5374.251203
• PMID: 30804242
• PMCID: 6425824
• Citations: 16
• Summary: Observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations, and that fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantOThenate treatment.
• Evidence snippets:
• Snippet 1 (score: 0.511) > Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can

[4] Exploring Yeast as a Study Model of Pantothenate Kinase-Associated Neurodegeneration and for the Identification of Therapeutic Compounds

• Authors: Camilla Ceccatelli Berti, A. I. Gilea, M. D. De Gregorio, P. Goffrini
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6fde3622ed03889ee246a5bd3b0fd36866fbeb98
• DOI: 10.3390/ijms22010293
• PMID: 33396642
• PMCID: 7795310
• Citations: 16
• Influential citations: 3
• Summary: A yeast model of PKAN recapitulates the main phenotypes associated with human disease, allowing a quick evaluation of the biochemical consequences of pantothenate kinase (PANK) protein variants could be a tool to predict genotype/phenotype correlation.
• Evidence snippets:
• Snippet 1 (score: 0.497) > Mutations in the pantothenate kinase 2 gene (PANK2) are the cause of pantothenate kinase-associated neurodegeneration (PKAN), the most common form of neurodegeneration with brain iron accumulation. Although different disease models have been created to investigate the pathogenic mechanism of PKAN, the cascade of molecular events resulting from CoA synthesis impairment is not completely understood. Moreover, for PKAN disease, only symptomatic treatments are available. Despite the lack of a neural system, Saccharomyces cerevisiae has been successfully used to decipher molecular mechanisms of many human disorders including neurodegenerative diseases as well as iron-related disorders. To gain insights into the molecular basis of PKAN, a yeast model of this disease was developed: a yeast strain with the unique gene encoding pantothenate kinase CAB1 deleted, and expressing a pathological variant of this enzyme. A detailed functional characterization demonstrated that this model recapitulates the main phenotypes associated with human disease: mitochondrial dysfunction, altered lipid metabolism, iron overload, and oxidative damage suggesting that the yeast model could represent a tool to provide information on pathophysiology of PKAN. Taking advantage of the impaired oxidative growth of this mutant strain, a screening for molecules able to rescue this phenotype was performed. Two molecules in particular were able to restore the multiple defects associated with PKAN deficiency and the rescue was not allele-specific. Furthermore, the construction and characterization of a set of mutant alleles, allowing a quick evaluation of the biochemical consequences of pantothenate kinase (PANK) protein variants could be a tool to predict genotype/phenotype correlation.

[5] Novel PANK2 mutation in a Chinese boy with PANK2-associated neurodegeneration

• Authors: Yingying Zhang, Dong Zhou, Tianhua Yang
• Year: 2019
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/8607326533731e001c73dc149795921f8e3e0bab
• DOI: 10.1097/MD.0000000000014122
• PMID: 30681573
• PMCID: 6358370
• Citations: 10
• Summary: It is indicated that atypical PKAN is the more common phenotype in China and no apparent genotype-phenotype correlation was found, and all PANK2 mutations reported in Chinese cases with PKAN were reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.476) > Pantothenate kinase associated neurodegeneration (PKAN) which is an autosomal recessive disease mutating from pantothenate kinase 2 gene (PANK2) manifests as progressive extrapyramidal dysfunction. [1] The feature of neuroimaging is "eye of the tiger sign" which is connected with brain iron accumulation in the globus pallidus. [2] PKAN is classified into 2 phenotypes: a "typical PKAN" with early onset (the first decade), speedy development and homogenous form in majority of the patients. An "atypical PKAN" with late onset, slow progression and variable clinical features. Compared to typical PKAN, atypical PKAN is characterized by more prominent speech problems, psychiatric symptom, much milder cognitive impairment and gait abnormalities. In addition, patients with atypical PKAN develop rarely retinopathy. > The PANK2 gene which is considered as main causative gene of PKAN is located on chromosome 20p13 and encodes pantothenate kinase-2 which plays an important role in coenzyme A (CoA) biosynthesis. It has been hypothesized that CoA deficiency due to PANK2 mutations might cause secondary accumulation of iron. [3] ut molecular mechanism of PKAN still remained unclear. > In this article, we reported the novel compound heterozygous PANK2 mutations of a Chinese boy with an atypical phenotype PKAN. In addition, we summarized clinical and genetic features of PKAN patients which were reported in Chinese population. > total DNA extraction from the proband, his parents and100 healthy controls were obtained after conformed consent.

[6] Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?

• Authors: Francesco Agostini, Bibiana Sgalletta, M. Bisaglia
• Year: 2024
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/631a7816a83f4dc7c213df8145bb6d8c78f2fd66
• DOI: 10.3390/cells13161376
• PMID: 39195264
• PMCID: 11352641
• Citations: 7
• Summary: The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology.
• Evidence snippets:
• Snippet 1 (score: 0.474) > Mitochondria are frequently regarded as the powerhouses of the cell due to their function as energy generators in the form of ATP [79]. However, their role goes far beyond that since they are cellular hubs that can influence different pathways and processes, such as autophagy and apoptosis [79]. For this reason, the conservation of mitochondrial quality control is essential to guarantee a balanced cellular homeostasis. In this scenario, it is not surprising that mitochondrial impairments are frequently associated with human diseases and are linked to neurodegeneration [80,81]. > Among the NBIA subtypes, the most common form of the pathology is caused by mutations in the pantothenate kinase 2 (PANK2) gene, which is responsible for the so-called Pantothenate Kinase-Associated Neurodegeneration (PKAN), a subtype of the disease with an estimated prevalence of three in one million [36,82]. More than 120 autosomal recessive mutations in this gene have been described as causing the reduction or complete loss of function of the PANK2 protein. Nevertheless, some mutations are associated with defects in PANK2 dimerization or loss of the mitochondrial targeting sequence, resulting in the cytosolic localization of the protein, suggesting that any type of disruption of this kinase function can lead to pathologic phenotypes [83,84]. This enzyme catalyzes the ATPdependent phosphorylation of pantothenate, an essential regulatory step in Coenzyme A (CoA) biosynthesis. PANK2 also acts as a sensor of mitochondrial CoA and is tightly regulated by the level of CoA and its thioesters through a negative feedback mechanism [85]. In the pathological context, this sensing function is not controlled and leads to energy impairments, ROS production and apoptosis [85]. Moreover, mice models for PKAN display mitochondrial membrane potential defects, increased mitochondrial ROS and enhanced iron levels [86]. In addition, lipid peroxidation, mitochondrial respiration deficits and premature cell death have been detected in neuronal cells generated from induced pluripotent stem cells (iPSCs) from PKAN patients [87,88].

[7] Therapeutic approach with commercial supplements for pantothenate kinase-associated neurodegeneration with residual PANK2 expression levels

• Authors: Mónica Álvarez-Córdoba, Diana Reche-López, Paula Cilleros-Holgado, Marta Talaverón-Rey, Irene Villalón-García et al.
• Year: 2022
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/a6ddbfea86059bc14e34792af76287ef51bd170b
• DOI: 10.1186/s13023-022-02465-9
• PMID: 35945593
• PMCID: 9364590
• Citations: 14
• Summary: Commercial supplements were able to eliminate iron accumulation, increase Pank2, mtACP, and NFS1 expression levels and improve pathological alterations in mutant cells with residual PANK2 expression levels, suggesting that several commercial compounds are indeed able to significantly correct the mutant phenotype in cellular models of PKAN.
• Evidence snippets:
• Snippet 1 (score: 0.473) > Thiamine treatment is very effective for some patients with PDH deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1) alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs [67][68][69][70][71]. > Interestingly, all the positive supplements identified in our work up-regulate PANK2 transcripts levels and increased key transcription factors, such as NF-Y, FOXN4 and hnRNPA/B, involved in PANK2 gene expression [23]. In addition, favorable supplements activate the expression of the key mitochondrial regulators such as PGC1α and TFAM [24][25][26]. Altogether, our data provide mechanistic insights into the mechanism of positive effect of pantothenate, pantethine, vitamin E, omega 3, carnitine and thiamine. > Given that the selected supplements are individually positive in PKAN cellular models, an interesting strategy would be to evaluate the individual and combined effect of these compounds in clinical practice. In fact, combination compounds that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug inefficiency and are the practice standard in many important therapeutic areas [72,73]. The limitations of many monotherapies can be overcome by targeting disease pathomechanisms on multiple fronts [74]. The systematic screening of combination of drugs in vitro can identify these multi-target mechanisms. Personalized screenings in patient-derived cellular model using active pharmaceutical ingredients can be especially valuable because potential synergies identified by these screens can rapidly move into preclinical and clinical development [75]. In addition, combination effects between compounds with known molecular targets can reveal unexpected relationships between disease pathways [76]. > Impaired mitochondrial function, excessive oxidative stress in human brain, genetic factors, and malfunction in human brain metabolism contribute to the progression of neurodegenerative diseases [77]. Multitarget therapeutics with antioxidant and mitochondrial boosting compounds hold promise in tackling the multifactorial and complex nature of neurodegenerative diseases such as PKAN [78,79].

[8] Down regulation of the expression of mitochondrial phosphopantetheinyl-proteins in pantothenate kinase-associated neurodegeneration: pathophysiological consequences and therapeutic perspectives

• Authors: Mónica Álvarez-Córdoba, Marta Talaverón-Rey, Irene Villalón-García, Suleva Povea-Cabello, J. M. Suárez-Rivero et al.
• Year: 2021
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/be44f4ebfe84dc897fb09254917c759b1f0db6d9
• DOI: 10.1186/s13023-021-01823-3
• PMID: 33952316
• PMCID: 8101147
• Citations: 18
• Influential citations: 1
• Summary: The results suggest that the expression levels of mitochondrial phosphopantetheinyl-proteins are severely reduced in PKAN cells and that in selected mutations pantothenate increases the expression Levels of both PANK2 and mitochondrial phosphOPantetheine cofactors associated with remarkable improvement of cell pathophysiology.
• Evidence snippets:
• Snippet 1 (score: 0.472) > The term Neurodegeneration with Brain Iron Accumulation (NBIA) refers to a group of genetic and progressive neurodegenerative diseases characterized by dystonia, rigidity, and choreoathetosis caused by iron accumulation in certain parts of the brain mainly basal ganglia [1,2]. Currently, 15 genes have been identified to cause the main clinical entities of NBIA [3]. However, the causative mutation is unknown in around 20% of cases [4]. > More than 50% of cases of NBIA are originated by mutations in the gene of pantothenate kinase 2 (PANK2) which encodes an essential enzyme in coenzyme A (CoA) biosynthesis [5]. This clinical subtype is termed pantothenate kinase-associated neurodegeneration (PKAN). The pantothenate kinase gene family includes PANK1a, PANK1b, PANK2 and PANK 3, but only the PANK2, is the gene responsible for PKAN. PANK2 enzyme is localized in mitochondrial intermembrane space and transforms (R)-pantothenate into (R)-4′-phosphopantothenate using ATP. > The enzyme alteration causes coenzyme A deficiency, mitochondria dysfunction and low energy production, intracellular iron accumulation, alterations in cell membranes renewal and impaired protection against oxidative damage, which provokes lipid peroxidation and pathological changes of cell membranes, and eventually cell demise [4,6]. Altered mitochondrial membrane potential and defective mitochondrial respiration have been demonstrated in PANK2-defective neurons derived from KO mice [7] and in cellular models derived from PKAN patients [8][9][10]. However, the precise pathological mechanisms involved in PKAN are not completely understood. > Apart of metabolic alterations including impairment of the citric acid cycle, sterol and steroid biosynthesis, heme biosynthesis, amino acid synthesis, and β-oxidation [11], low CoA levels particularly in mitochondria can also affect the 4′-phosphopantetheinylation of essential proteins for mitochondrial function and cell homeostasis [12].

[9] Proposed Therapies for Pantothenate-Kinase-Associated Neurodegeneration

• Authors: S. Jackowski
• Year: 2019
• Venue: Journal of Experimental Neuroscience
• URL: https://www.semanticscholar.org/paper/f44b229915a55d31eac3f145aa51211dc169e7dc
• DOI: 10.1177/1179069519851118
• PMID: 31205425
• PMCID: 6537486
• Citations: 13
• Influential citations: 2
• Summary: Evaluation of the biochemistry and medicinal chemistry of the proposed therapies for pantothenate-kinase-associated neurodegeneration reveals potential liabilities among several compounds under consideration for clinical development.
• Evidence snippets:
• Snippet 1 (score: 0.469) > Pantothenate-kinase-associated neurodegeneration (PKAN) is an inherited disease caused by PANK2 gene mutations 1 that are thought to result in the reduction of cellular coenzyme A (CoA). Patients with PKAN exhibit a variety of symptoms, including dystonia, rigidity, bradykinesia, spasticity, difficulty swallowing and speaking, shortened lifespan, and sometimes cognitive and visual impairment. 2 The clinical symptoms are often associated with an accumulation of iron in the brain and postmortem pathology indicates an enrichment of ischemic foci in the globus pallidus, 3 implicating an interruption of oxidative metabolism in the central nervous system (CNS). CoA is cell autonomous and thus any effective PKAN therapy must penetrate both cellular membranes and the blood-brain barrier (BBB). One of the first ideas was to treat patients with pantothenate in an attempt to raise CoA synthesis by increasing substrate supply. Although it remains possible that high-dose pantothenate over extended periods may be useful in reducing the symptoms, 4 the strong feedback inhibition of the pantothenate kinases (PANKs) means that there is little to no increase in tissue CoA levels in animals treated with high-dose pantothenate. 5 hree different approaches to PKAN therapy have been proposed that are designed to bypass the PANK2 genetic defect by supplying a CoA biosynthetic pathway intermediate downstream of PANK. Phosphopantothenate is the product of PANK but cannot cross cell membranes due to its charged nature. Fosmetpantotenate was designed as a prodrug to deliver phosphopantothenate to cells and elevate intracellular CoA. 6 The charged moieties on phosphopantothenate are chemically masked by covalent modification with hydrophobic groups to promote penetration across cellular membranes. The synthetic additions to phosphopantothenate are then released by intracellular enzymes (esterases) and the resulting phosphopantothenate bypasses PANK and is converted to CoA.

[10] Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

• Authors: Chiara Cavestro, D. Diodato, V. Tiranti, I. Di Meo
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/95487cfe46fce4ed7b310f5cdca5f4660746824c
• DOI: 10.3390/ijms24065951
• PMID: 36983025
• PMCID: 10054636
• Citations: 16
• Summary: A summary of CoA metabolism and functions is provided, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches are provided.
• Evidence snippets:
• Snippet 1 (score: 0.465) > Coenzyme A (CoA) is an essential, widely distributed cofactor that is crucial to cellular metabolism, playing a central role in the production and breakdown of all significant sources of energy in the body [1]. Its importance has recently been highlighted by the identification of four human pathologies linked to inborn errors of metabolism (IEM) in the CoA cellular de novo biosynthetic pathway. Although they are all caused by sequence variants in genes coding for enzymes involved in the same pathway, these four clinical conditions can be divided into two groups, as they are characterized by very distinct clinical symptoms. > Variants in the enzymes catalyzing the first (pantothenate kinase type 2, PANK2) and last (CoA synthase, COASY) reactions of the pathway are responsible for the neurological conditions called pantothenate kinase-associated neurodegeneration (PKAN) [2] and COASY protein-associated neurodegeneration (CoPAN) [3], respectively. These two diseases belong to a highly heterogeneous group of rare neurodegenerative diseases known as neurodegenerations with brain iron accumulation (NBIA), and they share some typical clinical features, including movement disorders, cognitive impairment, and iron accumulation in basal ganglia [4,5]. > A few years ago, a rapidly fatal dilated cardiomyopathy was linked to pathogenic variants in the second enzyme of the pathway (phosphopantothenoylcysteine synthetase, PPCS) with the discovery of three affected families [6,7]. Very recently, variants in the third enzyme of the pathway (phosphopantothenoylcysteine decarboxylase, PPCDC) were associated with a similar cardiac condition in two sisters [8]. > At present, little is known about these pathologies, especially those that have only recently been discovered. Mitochondria and peroxisomes are the two major subcellular storage sites for CoA and acyl-CoAs, and the investigations about the pathogenesis of the diseases have primarily involved these two compartments [9].

[11] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

• Authors: Xiao-lei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
• Year: 2025
• Venue: Signal Transduction and Targeted Therapy
• URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
• DOI: 10.1038/s41392-025-02179-x
• PMID: 40328798
• PMCID: 12056177
• Citations: 33
• Influential citations: 1
• Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
• Evidence snippets:
• Snippet 1 (score: 0.458) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[12] The Pathophysiological Role of CoA

• Authors: A. Czumaj, Sylwia Szrok-Jurga, Areta Hebanowska, Jacek Turyn, J. Świerczyṅski et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/d8191747843a08c344a245884cf9122f1267af94
• DOI: 10.3390/ijms21239057
• PMID: 33260564
• PMCID: 7731229
• Citations: 92
• Influential citations: 7
• Summary: The current knowledge of coenzyme A subcellular concentrations; the roles of CoA synthesis and degradation processes; and protein modification by reversible CoA binding to proteins (CoAlation) are summarized.
• Evidence snippets:
• Snippet 1 (score: 0.455) > Perhaps the best described disease associated with reduced cellular CoA-SH levels is pantothenate kinase-associated neurodegeneration (PKAN), also known as Hallervorden-Spatz disease, an autosomal recessive inherited disease caused by a mutation in the PANK2 gene. It was first described in 1922 by two physicians from Germany, Hallervorden and Spatz. This disease is characterized by neurodegeneration, iron accumulation in the brain, and variable neurological dysfunction. It is caused by specific mutation in the PANK2 gene that results in deficiency of the PANK2 enzyme, which leads to the accumulation of cysteine and the chelation of iron in the brain [95]. In vitro and animal studies confirmed that this disease is also associated with a decrease in CoA-SH and CoA thioesters in brain and liver cells [78,96]. The roles of CoA-SH levels in the development of PKAN have been presented in two recent papers. Lambrechts et al. [78] suggested that reduced CoA-SH biosynthesis leads to a reduction in active mitochondrial acyl carrier protein and the reduced lipoylation and activity of PDC. These findings were confirmed based on similar clinical features (e.g., progressive dystonia) of three other genetic diseases. Mutation of gene encoding another enzyme of the CoA-SH synthesis pathway, COASY, leads to CoA synthase protein-associated neurodegeneration (CoPAN), which is associated with partial loss of COASY activity. This disease has very similar clinical features to PKAN, including iron accumulation in the brain [97]. Two other CoA-related neurodegenerative diseases are not associated with CoA-SH synthesis: MePAN, which is caused by mutation of mitochondrial enoyl-[acyl carrier protein] reductase, a protein critical for lipoylation, and dihydrolipoyl transacetylase (PDC-E2) deficiency. All these pathologies result in decreased PDC activity [78].

[13] Natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration

• Authors: Xuting Chang, Jie Zhang, Yuwu Jiang, Jingmin Wang, Ye Wu
• Year: 2020
• Venue: CNS Neuroscience & Therapeutics
• URL: https://www.semanticscholar.org/paper/9dafb5e1cdd04e88ed106e5261de6bee2240bdf9
• DOI: 10.1111/cns.13294
• PMID: 32043823
• PMCID: 7298993
• Citations: 24
• Influential citations: 2
• Summary: To investigate the natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration, a genome-phenotype association study was conducted at the University of California, Berkeley.
• Evidence snippets:
• Snippet 1 (score: 0.453) > To investigate the natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration.

[14] Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

• Authors: P. Kotzbauer, A. Truax, J. Trojanowski, V. Lee
• Year: 2005
• Venue: The Journal of Neuroscience
• URL: https://www.semanticscholar.org/paper/51bdebd457459048c53e56aca1990940cd803ea2
• DOI: 10.1523/JNEUROSCI.4265-04.2005
• PMID: 15659606
• Citations: 163
• Influential citations: 6
• Summary: It is demonstrated that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences.
• Evidence snippets:
• Snippet 1 (score: 0.448) > Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5′ start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.

[15] Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration

• Authors: L. Mignani, D. Zizioli, D. Khatri, N. Facchinello, Marco Schiavone et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/78ddd7487f722cf411f9edacbac252cb9efba1c0
• DOI: 10.3390/ijms232112914
• PMID: 36361705
• PMCID: 9657214
• Citations: 6
• Summary: The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish, andiphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN.
• Evidence snippets:
• Snippet 1 (score: 0.448) > Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration (PKAN), one of the most common forms of neurodegeneration, with brain iron accumulation. Knowledge about the biochemical and molecular features of this disorder has increased a lot in recent years. Nonetheless, the main culprit of the pathology is not well defined, and no treatment option is available yet. In order to contribute to the understanding of this disease and facilitate the search for therapies, we explored the potential of the zebrafish animal model and generated lines carrying biallelic mutations in the pank2 gene. The phenotypic characterization of pank2-mutant embryos revealed anomalies in the development of venous vascular structures and germ cells. Adult fish showed testicular atrophy and altered behavioral response in an anxiety test but no evident signs of neurodegeneration. The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish. Deciphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN.

[16] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

• Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
• Year: 2024
• Venue: International Journal For Multidisciplinary Research
• URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
• DOI: 10.36948/ijfmr.2024.v06i03.19194
• Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.440) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[17] Characterization of the Pank2-/- mouse retinal phenotype as a pre-clinical model for pantothenate kinase-associated neurodegeneration

• Authors: G. Su, S. Y. Jeong, Dahlia Wafai, Wayne Tschetter, Dolly Zhen et al.
• Year: 2025
• Venue: PLOS One
• URL: https://www.semanticscholar.org/paper/800b2c0bdbd013c3446f2c1ad897733b5ab82937
• DOI: 10.1371/journal.pone.0326866
• PMID: 40554626
• PMCID: 12186889
• Summary: The longitudinal characterization of the retinopathy in this mouse model reveals reduced visual performance and reduced photoreceptor thickness compared to wild-type mice, and retinal perturbations in coenzyme A metabolism and dopamine metabolism pathways mimic those previously observed in the brain.
• Evidence snippets:
• Snippet 1 (score: 0.440) > Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive movement and vision disorder in the neurodegeneration with brain iron accumulation family of diseases. PKAN is caused by mutations in PANK2, encoding pantothenate kinase 2, causing an inborn error of coenzyme A metabolism and leading to iron accumulation in the basal ganglia. Peripheral pigmentary retinopathy is common in people with PKAN. The knockout murine model of the orthologous Pank2 gene is known to manifest retinal degeneration through electroretinography, pupillary response and histology analyses. Our longitudinal characterization of the retinopathy in this model reveals reduced visual performance and reduced photoreceptor thickness compared to wild-type mice. Additionally, retinal perturbations in coenzyme A metabolism and dopamine metabolism pathways mimic those previously observed in the brain. These data extend the murine ocular phenotype associated with loss of function of Pank2. With a measurable behavioral, structural and mechanistic retinal phenotype, this mouse model is an ideal pre-clinical model that can be used to evaluate therapeutics for PKAN.

[18] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

• Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
• Year: 2024
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
• DOI: 10.3389/fphar.2024.1397864
• PMID: 38846086
• PMCID: 11154008
• Citations: 3
• Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
• Evidence snippets:
• Snippet 1 (score: 0.434) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[19] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

• Authors: M. M. Wong, L. Watson, Esther B. E. Becker
• Year: 2017
• Venue: Journal of neurology & neuromedicine
• URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
• DOI: 10.29245/2572.942X/2017/7.1134
• PMID: 28825058
• PMCID: 5558869
• Citations: 9
• Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
• Evidence snippets:
• Snippet 1 (score: 0.427) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.