A therapeutic approach to pantothenate kinase associated neurodegeneration

Sharma, Lalit Kumar; Subramanian, Chitra; Yun, Mi‐Kyung; Frank, Matthew W.; White, Stephen W.; Rock, Charles O.; Lee, Richard; Jackowski, Suzanne

doi:10.1038/s41467-018-06703-2

Cited by 77 publications

(133 citation statements)

References 56 publications

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“…Being easily available, erythrocytes could turn out to be useful in studies on the cellular effects of novel PKAN drugs. 27,28 More generally, since recent analyses revealed a yet unrecognized Figure 4. Conservation of PANK2 point mutations sites between the isoforms and phylogenetic variation within a partial sequence corresponding to the region around T528 of human PANK2.…”

Section: Discussionmentioning

confidence: 99%

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

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Müllner

Mlynek

et al. 2020

Ann Clin Transl Neurol

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

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Section: Discussionmentioning

confidence: 99%

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Werning

Müllner

Mlynek

et al. 2020

Ann Clin Transl Neurol

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“…The anti‐PANK antibody recognized all human PANK isoforms and AtPANK4. The anti‐PANK antibody was validated by immunoblotting serial dilutions of the purified antibody preparations against purified recombinant mouse PanK1α, PanK1β, PanK2, and PanK3 proteins . The CmPANK4 and the NpPANK4 were blotted with anti‐His probe.…”

Section: Methodsmentioning

confidence: 99%

“…The total CoA levels were determined using monobromobimane derivatization and HPLC analysis as previously described. 57 The expression of the constructs was checked via Western blot analysis using either a mouse monoclonal anti-polyhistidine-alkaline phosphatase antibody (Sigma, A5588) or a rabbit polyclonal, affinity purified anti-PANK antibody 58 coupled with goat anti-rabbit IgG-alkaline phosphatase from Sigma (A3687) and exposed using the ECF substrate (GE Healthcare). The anti-PANK antibody recognized all human PANK isoforms and AtPANK4.…”

Section: Hek 293t Cell Expressionmentioning

confidence: 99%

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

et al. 2019

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Pantothenate kinase generates 4′‐phosphopantothenate in the first and rate‐determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well‐characterized and nearly identical pantothenate kinases (PANK1‐3) plus a putative bifunctional protein (PANK4) with a predicted amino‐terminal pantothenate kinase domain fused to a carboxy‐terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Biochemical analysis corroborates bioinformatic predictions—human PANK4 lacks pantothenate kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust pantothenate kinase activity. Introducing both catalytic residues back into human PANK4 restored kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of kinase activity, supporting the view that HsPANK4 had reduced kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo‐pantothenate kinase—a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the pantothenate kinase activity that had already been reduced by prior epistatic mutations.

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“…Recently, a review on clinical trials using deferiprone has reflected that although accumulated iron decreased in the GP, motor symptoms, such as dystonia, do not seem to improve: the effect of deferiprone is practically non-existent in patients with the classical phenotype, whereas patients with the atypical form present with a slower progression [ 72 ]. Regarding PANK2 activity, direct supplementation of pantothenate is effective in high doses in KO mice; however, a CoA deficiency is produced in many tissues by inhibition of the rest of PANKs [ 73 ], and as expected, pantothenate has no effect on fibroblasts derived from patients with truncated PANK2 [ 74 ]. Different compounds have been tested in order to increase the CoA levels without having to go through the classic PANK2 route.…”

Section: Nbia Errors Of Coenzyme a Biosynthesismentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

et al. 2020

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The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

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A therapeutic approach to pantothenate kinase associated neurodegeneration

Cited by 77 publications

References 56 publications

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

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