NBIA (neurodegeneration with brain iron accumulation) comprises a heterogeneous group of neurodegenerative diseases having as a common denominator, iron overload in specific brain areas, mainly basal ganglia and globus pallidus. In the past decade a bunch of disease genes have been identified, but NBIA pathomechanisms are still not completely clear. PKAN (pantothenate kinase-associated neurodegeneration), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA. It is caused by mutations in the PANK2 (pantothenate kinase 2) gene, coding for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the CoA (coenzyme A) biosynthetic pathway. A distinct form of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration), is caused by mutations in the CoASY (CoA synthase) gene coding for a bifunctional mitochondrial enzyme, which catalyses the final steps of CoA biosynthesis. These two inborn errors of CoA metabolism further support the concept that dysfunctions in CoA synthesis may play a crucial role in the pathogenesis of NBIA.

Introduction

To date, ten genes have been associated with specific forms of NBIA (neurodegeneration with brain iron accumulation) [1]. As reported in Table 1, only two forms are caused by mutations in genes coding for proteins directly involved in iron metabolism: neuroferritinopathy due to FTL (ferritin light) chain gene (MIM #606159) mutation [2] and acaeruloplasminaemia linked to mutations in the CP (caeruloplasmin) gene (MIM #117700) [3]. The other NBIA disease genes encode proteins with a variety of functions: some are involved in fatty acid metabolism and autophagy while others have still unknown roles (Table 1).

Table 1
NBIA disorders and associated genes

The Table summarizes the currently known genes involved in NBIA. FTL, ferritin light polypeptide; CP, caeruloplasmin; PANK2, pantothenate kinase 2; PLA2G6, phospholipase A2; C19orf12, chromosome 19 open reading frame 12; FA2H, fatty acid 2 hydroxylase; ATP13A2, ATPase type 13A2; DCAF17, DDB1- and CUL4-associated factor 17; WDR45, WD40 repeat domain 45; COASY, CoA synthase.

DiseaseDisease geneInheritanceSymptoms
Neuroferritinopathy FTL (19q13.3) Autosomal dominant Extrapyramidal signs, dystonia, orofacial dystonia, cognitive decline 
Acaeruloplasminaemia CP (3q23.25) Autosomal recessive Iron not only in the basal ganglia, but also in liver, pancreas and myocardium; cognitive impairment, diabetes mellitus, retinal degeneration, blepharospasm, facial and neck dystonia, chorea, dysarthria, ataxia 
PKAN PANK2 (20p12.3) Autosomal recessive Dystonia, spasticity, cognitive decline, pigmentary retinopathy 
PLA2G6-associated neurodegeneration (PLAN) PLA2G6 (22q12.13) Autosomal recessive Infantile neuroaxonal dystrophy, progressive motor and mental retardation, cerebellar ataxia, pyramidal signs 
Mitochondrial membrane protein-associated neurodegeneration (MPAN) C19orf12 (19q12) Autosomal recessive Iron-containing deposits, dystonia, parkinsonism, psychiatric symptoms, spastic paraparesis 
FA2H-ssociated neurodegeneration (FAHN) FA2H (16q23) Autosomal recessive Spastic quadriparesis, severe ataxia, dystonia 
Kufor–Rakeb disease ATP13A2 (1p36) Autosomal recessive Early-onset levodopa-responsive parkinsonism with pyramidal tract involvement, dementia 
Woodhouse–Sakati syndrome DCAF17 (2q31.1) Autosomal recessive Hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, electrocardiographic abnormalities 
β-Propeller protein-associated neurodegeneration (BPAN) WDR45 (Xp11.23) X-linked Cognitive impairment, progressive dystonia-parkinsonism, corticospinal signs 
CoPAN COASY (17q12.21) Autosomal recessive Oro-mandibular dystonia, dysarthria, spastic dystonic paraparesis, obsessive-compulsive behaviour 
DiseaseDisease geneInheritanceSymptoms
Neuroferritinopathy FTL (19q13.3) Autosomal dominant Extrapyramidal signs, dystonia, orofacial dystonia, cognitive decline 
Acaeruloplasminaemia CP (3q23.25) Autosomal recessive Iron not only in the basal ganglia, but also in liver, pancreas and myocardium; cognitive impairment, diabetes mellitus, retinal degeneration, blepharospasm, facial and neck dystonia, chorea, dysarthria, ataxia 
PKAN PANK2 (20p12.3) Autosomal recessive Dystonia, spasticity, cognitive decline, pigmentary retinopathy 
PLA2G6-associated neurodegeneration (PLAN) PLA2G6 (22q12.13) Autosomal recessive Infantile neuroaxonal dystrophy, progressive motor and mental retardation, cerebellar ataxia, pyramidal signs 
Mitochondrial membrane protein-associated neurodegeneration (MPAN) C19orf12 (19q12) Autosomal recessive Iron-containing deposits, dystonia, parkinsonism, psychiatric symptoms, spastic paraparesis 
FA2H-ssociated neurodegeneration (FAHN) FA2H (16q23) Autosomal recessive Spastic quadriparesis, severe ataxia, dystonia 
Kufor–Rakeb disease ATP13A2 (1p36) Autosomal recessive Early-onset levodopa-responsive parkinsonism with pyramidal tract involvement, dementia 
Woodhouse–Sakati syndrome DCAF17 (2q31.1) Autosomal recessive Hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, electrocardiographic abnormalities 
β-Propeller protein-associated neurodegeneration (BPAN) WDR45 (Xp11.23) X-linked Cognitive impairment, progressive dystonia-parkinsonism, corticospinal signs 
CoPAN COASY (17q12.21) Autosomal recessive Oro-mandibular dystonia, dysarthria, spastic dystonic paraparesis, obsessive-compulsive behaviour 

PKAN (pantothenate kinase-associated neurodegeneration) accounts for approximately 50% of NBIA cases and is caused by mutations in the PANK2 (pantothenate kinase type 2) gene, whereas, recently, a novel subtype of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration) (MIM #609855), has been associated with mutations in the CoASY (CoA synthase) gene [4]. As a high-energy carrier of acetyl and acyl groups, CoA (coenzyme A) is central to diverse cellular metabolic processes including citric acid cycle, fatty acid biosynthesis, β-oxidation, cholesterol and sphingolipid synthesis. In addition, CoA is a crucial factor in regulating a variety of enzymatic reactions and cellular metabolic processes. A reduction in CoA levels has been demonstrated in PANK-deficient Drosophila fumble mutants [5] and in mice lacking both Pank1 and Pank2 genes [6]. Moreover, the demonstration of CoASY interaction with components of the PI3K/mTOR/S6K (phosphoinositide 3-kinase/mammalian target of rapamycin/S6 kinase) signalling cascade suggests an interesting link between CoA biosynthesis and the regulation of cellular metabolism [7,8].

Here we will discuss the main features of PANK2 and CoASY, and their relationship with CoA metabolism and neurodegeneration.

CoA

CoA is an indispensable cofactor in all living organisms, where it functions as an acyl group carrier and carbonyl-activating group in a multitude of biochemical transformations, including the TCA (tricarboxylic acid) cycle and fatty acid metabolism. De novo synthesis of CoA is a highly conserved pathway that includes five enzymatic steps: pantothenic acid (vitamin B5) phosphorylation, cysteine conjugation, decarboxylation, conjugation to an adenosyl group and phosphorylation. In mammals, the first step is catalysed by PANK, whereas the last two steps are catalysed by CoASY, a mitochondrial bifunctional enzyme endowed with both PPAT (4′-phosphopantetheine adenylyltransferase) and DPCK (dephospho-CoA kinase) activities.

The reaction catalysed by PANK is the primary rate-limiting step in CoA biosynthesis and it is controlled by CoA and CoA thioesters the end-products of the pathway. Feedback regulation of PANK by different CoA molecular species controls overall CoA availability in response to cell metabolic status. In bacteria, a second level of regulation is evident at PPAT (or CoAD). CoA consists of 3′-phosphoadenosine linked through the 5′ position of the ribose, to pantothenic acid via pyrophosphate linkage. The carboxyl end of pantothenic acid is linked through a peptidic link to 2-mercaptoethanol amine. The thiol group at the end is essential to the chemical reactions in which CoA is involved, so the enzymes involved in CoA biosynthesis are very specific in incorporating cysteine, but not other amino acids [9]. CoA is utilized in about 100 biosynthetic and degrading reactions. Over 4% of cellular reactions utilize CoA. Tissue levels can vary widely depending on the organ in question, diet and fed/fasting state. The ratio of free CoA to acyl-CoA is important for regulating many key metabolic enzymes, such as acyl-CoA synthetase, PDH (pyruvate dehydrogenase) and 2-OG (2-oxoglutarate) dehydrogenase. The level of CoA is regulated by numerous extracellular stimuli, including hormones, glucocorticoids, nutrients and cellular metabolites [10].

In plants, the steps that convert pantothenate into CoA are almost certainly cytosolic [11,12]. CoA is required in mitochondria for the citric acid cycle, in chloroplasts for fatty acid synthesis, and in peroxisomes for β-oxidation. CoA must be imported into these organelles from the cytosol. Yeast and mammalian mitochondria and peroxisomes likewise import CoA because they cannot make it [13]. Mitochondrial CoA transporters belonging to the MCF (mitochondrial carrier family) have been identified in yeast [14] and humans [15]. The compartmentalization of CoA in all eukaryotes appears to be closely regulated, with cytosol and organelles maintaining separate CoA pools whose levels can modulate fluxes through CoA-dependent reactions. Mammalian cytosolic concentrations are estimated to be in the range 0.02–0.14 mM in animal tissues, whereas mitochondrial concentrations are much higher: from 2 to over 5 mM [16].

PANK2

Approximately half of the NBIA cases can be explained by PANK2 gene mutations causing PKAN. By linkage analysis, the defective gene was mapped to chromosome 20p12.3 [17]. Early onset is associated with the classic presentation, whereas patients with later onset often show atypical features. There are differences in expression pattern among the PANK genes. PANK1 is expressed in heart, liver and kidney, whereas PANK3 is expressed most abundantly in the liver. In contrast with these two genes, PANK2 is ubiquitously expressed, including in retina and infant basal ganglia [17]. PANK2 dysfunction is compatible with life, and two functional homologues, PANK1 and PANK3, encode proteins located in the cytosol and may compensate for the loss of PANK2. There is also a PANK4 protein, which is fairly dissimilar from PANK1, PANK2 and PANK3 and apparently lacks enzymatic activity. Human full-length PANK2 is cleaved at two sites by the mitochondrial processing peptidase, generating a transient 59.2 kDa intermediate and a long-lived 47.4 kDa mature protein. Mitochondrial targeting sequences are located in both the largest precursor peptide and the intermediate peptide, and the biochemical activity of the 48 kDa protein is confirmed [18]. Investigations of human PANK2 expression indicated two different transcripts, predicted to encode two protein isoforms; the longest PANK2 isoform localizes to mitochondria [19].

PANK is known to catalyse the first out of five steps in CoA biosynthesis, which utilizes pantothenate, cysteine and ATP. CoA is synthesized from vitamin B5 or pantothenate, which is taken up by endothelial cells via a sodium-dependent multivitamin transporter and then passes to the blood for delivery to the rest of the body. Mutations in PANK2 are expected to result in defective CoA biosynthesis, which could lead to a variety of metabolic defects. Recently it has been hypothesized that diminished CoA pools have injurious effects on histone and tubulin acetylation, contributing to the neurological phenotype of PKAN [20]. However, it is not known how mutations in PANK2 cause the spectrum of clinical symptoms exhibited by PKAN patients. Iron was increased in the cytoplasm of degenerating neurons, implying that neurons manifest iron overload before their degeneration and that iron overload may contribute to neuronal loss in PKAN [21]. In a recent study, the ‘eye of the tiger’ was identified as an ovoid region in the globus pallidus that was markedly depleted of viable neurons, but rich in large spheroids that consisted of degenerating neurons, and smaller spheroids composed of dystrophic axons [21]. MRI studies on pre-symptomatic patients with PKAN [21] may support the possibility that neuronal loss precedes iron accumulation and that iron accumulation may be a secondary effect.

A metabolic study on plasma derived from PKAN patients, has reported reduced lipid and cholesterol biosynthesis, impaired bile acid metabolism and reduced levels of certain sphingomyelin species [22]. Sphingomyelins are the principal component of the myelin sheath wrapping the axons of neuronal cells [22]. A recent study investigated the metabolic phenotype in PKAN patients in order to address questions of energy balance, nutrition status and lipid metabolism [23]. The study of PANK2 function is complex. The generation of animal models of disease by knocking out the gene in fruitflies and mice have generated incomplete phenotypes, lacking signs of NBIA. A PKAN model of Drosophila has a brain phenotype characterized by the formation of vacuoles, but the presence or absence of iron was never demonstrated [24]. This model has shown mitochondrial dysfunction, decreased levels of CoA, increased protein oxidation and reduced lifespan [24]. Interestingly, it was demonstrated that these alterations could be rescued by providing pantethine in the diet [5]. In 2005, Pank2-null mice were generated [25], which showed growth reduction, retinal degeneration and male infertility due to azoospermia, but no movement disorder or brain iron accumulation, investigated by MRI and Perl's DAB (3,3′-diaminobenzidine) staining, even after 18 months of age [25]. In contrast, a pantothenic acid-deficient diet was able to elicit a movement disorder and azoospermia in mice without evidence of iron accumulation in brain [26]. Human and mouse PANK2 proteins show an identity of 90%, although the mouse polypeptide does not have an N-terminal extension, which is present in human PANK2. A recent study has demonstrated that murine PANK2 is mainly located in the mitochondrial inter-membrane space [27] as is the human protein [28]. Pank2-null mice show alteration of mitochondrial membrane potential in neurons derived from sciatic nerve and hair bulge stem cells of adult mice. The same alteration is also present in neonatal hippocampal neurons. Electron microscopy analysis on cultured neurons derived from Pank2-null mice, has shown aberrant swollen mitochondria with remodelled cristae [27]. On the basis of the role of CoA in several crucial metabolic pathways and considering the data obtained by the metabolomics study in patients with PKAN [22] indicating the presence of impairment in lipid metabolism, a recent work tested the hypothesis by challenging a Pank2-null mouse model with a diet containing high fat levels. A ketogenic diet consists of a low-glucose and high-lipid content, stimulating lipid use by mitochondrial β-oxidation and ketone body production in the liver. Pank2-null mice on a ketogenic diet demonstrated the clinical signs present in patients with PKAN, namely more severe movement disorder and neurodegeneration. Pantethine administration to these mice resulted in a rescue of the clinical phenotype [29] including the movement disorder and the extension of lifespan as previously demonstrated in Drosophila [5]. It is known that pantethine is rapidly converted into cysteamine and pantothenate by pantetheinase [30]. Although pantethine is not able to cross the blood–brain barrier, cysteamine can cross the blood–brain barrier and can exert positive effects on the striatum and substantia nigra [31]. These data, together with data obtained in the PKAN Drosophila model, strongly suggest that pantethine administration to patients with PKAN should be considered as a possible and non-toxic therapeutic approach.

CoASY

A recent finding of human CoASY mutations in NBIA renews interest in CoA biosynthesis. In fact, in humans, CoASY is a mitochondrial bifunctional enzyme of 62 kDa, with both PPAT and DPCK activities involved in the last two reactions of de novo CoA synthesis [32]. Although CoASY does not share a significant amino acidic sequence similarity with prokaryotes, a missense CoASY mutation identified in NBIA patients [4] involves a residue highly conserved from bacteria to humans. In prokaryotes, plants and fungi, the PPAT and DPCK proteins are encoded by two different genes. PPAT, also named CoAD, catalyses the transfer of an adenylyl group from ATP to 4-phospho-pantethine and appears as a homohexamer arranged in a dimer of trimers. It seems to be the second point of biosynthesis regulation [33]. To investigate the mechanism of this regulation, crystal structures of bacterial PPAT have been determined in the presence of substrates and products. These studies show preferential binding of the molecules with only one of the two dimers, creating asymmetric units, and demonstrate an allosteric mechanism of catalysis [34,35]. Moreover, the crystal structure of PPAT-CoA mimics the PPAT-dPCoA (3′-dephospho-CoA) and PPAT-Ppant (4′-phosphopantetheinyl), showing similar conformational changes that prevent any other substrate interaction and suggesting that the asymmetry of binding of CoA plays a role in negative feedback regulation [36,37].

DPCK, also named CoAE, catalyses the phosphorylation of the 3′ hydroxy group of ribose using ATP as a phosphate donor and appears in solution and in crystal structure respectively as a monomer in Haemophilus influenzae [38] or as a homotrimer in bacteria [39]. Despite their difference in quaternary structure, the sequence of DPCK in these micro-organisms shares 48% homology and has a very similar tertiary structure with several differences localized in residues involved in trimerization. The crystal reveals three conserved domains, typical of nucleosides kinase: the nucleotide-binding domain or P-loop; the substrate-binding domain; the lid domain. Interestingly, one of the human CoASY mutations is localized in the P-loop conserved domain [4], so further crystallization studies are necessary to understand the structure and regulation of the protein.

Conclusions and future perspectives

The aim of the present review was to highlight the importance of the discovery of a second inborn error in the CoA pathway associated with NBIA and to underline the potential link between CoA synthesis and neurodegeneration.

It is evident that two different and crucial pathways, namely CoA biosynthesis and iron metabolism, which are apparently not connected, play a crucial role in the pathogenesis of NBIA. CoA is an essential metabolic cofactor, which is involved in a wide variety of metabolic processes. On the other hand, regulation of iron metabolism is also crucial since both iron deficiency and iron overload can cause diseases. Some researchers have hypothesized that iron accumulation may be just an epiphenomenon, and not a primary cause of NBIA diseases [40]. During the normal aging process, brain iron accumulation is present in healthy people, but it is also associated with various neurodegenerative diseases, such as Parkinson's disease, AD (Alzheimer's disease) and multiple sclerosis [41]. Iron has been identified as a potential damaging element for tissues either directly or because it changes the cellular environment, making it more prone to toxins. On the other hand, iron deposition may be just a consequence of microglial response to neuronal death and may not have a causative role in disease [42]. In addition, it remains unexplained why mutations in the enzymes involved in the CoA biosynthetic pathway cause neurodegeneration. The hypothesis of cysteine accumulation, due to PANK2 malfunctioning, which produces free radical formation, appears plausible, but the pathophysiology of PKAN is not understood [43].

Moreover, it is necessary to find a different mechanism to explain the role of CoASY mutations.

This new finding, of human CoASY mutations in NBIA, supports the idea that a dysfunction in CoA synthesis plays a crucial role in the pathogenesis of NBIA and thus in the development and functioning of the nervous system. This was previously suggested by other studies: the PKAN Drosophila model manifests neurological symptoms and a significant decrease of CoA levels [5], and CoA level is reduced in mice lacking both Pank1 and Pank2 genes [6]. In addition, it has been demonstrated that CoASY associates specifically with S6K, a kinase regulator of cell size and growth, which is activated in response to mitogenic stimuli and nutrients via PI3K and mTOR signalling pathways [7,8].

Moreover, a recent study shows that the inhibition of acetyl-CoA synthesis induces autophagy, whereas stimulation of acetyl-CoA synthesis inhibits autophagy induced by different stimuli [44].

Nevertheless, further investigations are necessary to find a connection between CoA metabolism, lipid metabolism and mitochondrial dysfunctions, due to the mitochondrial localization of both PANK2 and CoASY [4,4548]. Additional research will be required to better define the sub-mitochondrial compartments in which PANK2 and CoASY are located and to understand whether the other enzymes of CoA biosynthesis, PPCDC (phosphopantothenoylcysteine decarboxylase) and PPCS (phosphopantothenoylcysteine synthetase), are exclusively present in the cytoplasm. It would be relevant to clarify whether an exclusively mitochondrial CoA biosynthetic pathway is present and how the exchange of CoA between the different cellular compartments is regulated.

These studies will pave the way to understanding the molecular mechanisms involved in CoA metabolism and its connection with iron management in the brain, mitochondrial function and neurodegeneration.

Coenzyme A and Its Derivatives in Cellular Metabolism and Disease: A Biochemical Society Focused Meeting held at Charles Darwin House, London, U.K., 20–21 March 2014. Organized and Edited by Ivan Gout (University College London, U.K.), Suzanne Jackowski (St. Jude Children's Research Hospital, U.S.A.) and Ody Sibon (University of Groningen, The Netherlands).

Abbreviations

     
  • CoASY

    CoA synthase

  •  
  • CoPAN

    CoA synthase protein-associated neurodegeneration

  •  
  • DPCK

    dephospho-CoA kinase

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • NBIA

    neurodegeneration with brain iron accumulation

  •  
  • PANK

    pantothenate kinase

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PKAN

    pantothenate kinase-associated neurodegeneration

  •  
  • PPAT

    4′-phosphopantetheine adenylyltransferase

  •  
  • S6K

    S6 kinase

Funding

The support of Telethon [grant number GGP11088 (to V.T.)] and of Mariani Foundation of Milan is gratefully acknowledged. This work was supported by TIRCON project of the European Commission's Seventh Framework Programme (FP7/2007–2013, HEALTH-F2-2011) [grant number 277984].

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