Role of genetic modifiers in Lafora progressive myoclonus epilepsy-a neurodegenerative disorder with defects in carbohydrate metabolism

We have considered it appropriate to publish this case due to the rarity of progressive myoclonus epilepsy; diagnostic difficulties, particularly in the early stages of the disease (the female patient has been long followed up for diagnosed juvenile myoclonic epilepsy); the relative role of a genetic study because it has not brought results in this case, and, finally, a problem with therapy, and a significant contribution to the achievement of certain success of currently available antiepileptic drugs, levetiracetam in particular.

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Possible Mechanisms by which Stefin B could Regulate Proteostasis and Oxidative Stress

Cells ◽

10.3390/cells8010070 ◽

2019 ◽

Vol 8 (1) ◽

pp. 70 ◽

Cited By ~ 2

Author(s):

Eva Žerovnik

Keyword(s):

Oxidative Stress ◽

Protease Inhibitor ◽

Protein Aggregates ◽

Misfolded Proteins ◽

Progressive Myoclonus Epilepsy ◽

The Family ◽

Myoclonus Epilepsy ◽

And Oxidative Stress

Human stefin B is a protease inhibitor from the family of cystatins. It was reported that it forms oligomers in cells. We have shown that it has a role in cell’s response to misfolded proteins. We also have shown that its oligomers bind amyloid-beta (Aβ). Here, we discuss ways, how stefin B could reduce build-up of protein aggregates by other proteins and consequently reduces ROS and, how this might be connected to autophagy. When overexpressed, stefin B forms protein aggregates itself and these protein aggregates induce autophagy. Similarly, cystatin C was shown to bind Aβ and to induce autophagy. It is also suggested how more knowledge about the role of stefin B in a cell’s response to misfolded proteins could be used to modulate progressive myoclonus epilepsy of type 1 EPM1 disease.

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Lafora Disease: A Review of Molecular Mechanisms and Pathology

Neuropediatrics ◽

10.1055/s-0038-1675238 ◽

2018 ◽

Vol 49 (06) ◽

pp. 357-362 ◽

Cited By ~ 5

Author(s):

Brandy Verhalen ◽

Susan Arnold ◽

Berge Minassian

Keyword(s):

Ubiquitin Ligase ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Vegetative State ◽

Glycogen Synthesis ◽

Loss Of Function ◽

Lafora Disease ◽

Lafora Bodies ◽

Progressive Myoclonus Epilepsy ◽

Myoclonus Epilepsy

AbstractLafora's disease is a neurodegenerative disorder caused by recessive loss-of-function mutations in the EPM2A (laforin glycogen phosphatase) or EPM2B (malin E3 ubiquitin ligase) genes. Neuropathology is characterized by malformed precipitated glycogen aggregates termed Lafora bodies. Asymptomatic until adolescence, patients undergo first insidious then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade. Laforin and malin interact to regulate glycogen phosphorylation and chain length pattern, the latter critical to glycogen's solubility. Significant gaps remain in precise mechanistic understanding. However, demonstration that partial reduction in brain glycogen synthesis near-completely prevents the disease in its genetic animal models opens a direct present path to therapy.

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Deciphering the role of malin in the lafora progressive myoclonus epilepsy

IUBMB Life ◽

10.1002/iub.1072 ◽

2012 ◽

Vol 64 (10) ◽

pp. 801-808 ◽

Cited By ~ 20

Author(s):

Carlos Romá-Mateo ◽

Pascual Sanz ◽

Matthew S. Gentry

Keyword(s):

Progressive Myoclonus Epilepsy ◽

Myoclonus Epilepsy

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A KCNC1 mutation in Epilepsy of Infancy with Focal Migrating Seizures produces functional channels that fail to be regulated by phosphorylation

Journal of Neurophysiology ◽

10.1152/jn.00257.2021 ◽

2021 ◽

Author(s):

Yalan Zhang ◽

Syed R Ali ◽

Rima Nabbout ◽

Giulia Barcia ◽

Leonard K. Kaczmarek

Keyword(s):

De Novo ◽

Channel Modulation ◽

Progressive Myoclonus Epilepsy ◽

C Terminus ◽

Myoclonus Epilepsy ◽

Voltage Dependent ◽

Genes Encoding ◽

Clear Change

Channelopathies caused by mutations in genes encoding ion channels generally produce a clear change in channel function. Accordingly, mutations in KCNC1, which encodes the voltage-dependent Kv3.1 potassium channel, result in Progressive Myoclonus Epilepsy as well as other Developmental and Epileptic Encephalopathies, and these have been shown to reduce or fully abolish current amplitude. One exception to this is the mutation A513V Kv3.1b, located in the cytoplasmic C-terminal domain of the channel protein. This de novo variant was detected in a patient with Epilepsy of Infancy with Focal Migrating Seizures (EIFMS) but no difference could be detected between A513V Kv3.1 current and that of wild type Kv3.1. Using both biochemical and electrophysiological approaches, we have now confirmed that this variant produces functional channels but find that the A513V mutation renders the channel completely insensitive to regulation by phosphorylation at S503, a nearby regulatory site in the C-terminus. In this respect, the mutation resembles those in another channel, KCNT1, which are the major cause of EIFMS. Because the amplitude of Kv3.1 current is constantly adjusted by phosphorylation in vivo, our findings suggest that loss of such regulation contributes to EIFMS phenotype and emphasize the role of channel modulation for normal neuronal function.

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Progressive myoclonus epilepsy: a differential diagnosis from juvenile chorea Huntington disease

Neuropediatrics ◽

10.1055/s-0033-1337705 ◽

2013 ◽

Vol 44 (02) ◽

Author(s):

M Gosk ◽

F Laccone ◽

P Burfeind ◽

G Bernert

Keyword(s):

Differential Diagnosis ◽

Huntington Disease ◽

Chorea Huntington ◽

Progressive Myoclonus Epilepsy ◽

Myoclonus Epilepsy

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Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666181009161048 ◽

2019 ◽

Vol 26 (20) ◽

pp. 3719-3753 ◽

Cited By ~ 10

Author(s):

Natasa Kustrimovic ◽

Franca Marino ◽

Marco Cosentino

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Immune System ◽

Neurodegenerative Disorder ◽

Neurodegenerative Process ◽

Progressive Degeneration ◽

Cytokine Levels ◽

Inflammatory Phenotype ◽

Immune Challenges

:Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.:In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

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Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽

10.3390/antiox10030357 ◽

2021 ◽

Vol 10 (3) ◽

pp. 357

Author(s):

Mojca Trstenjak Prebanda ◽

Petra Matjan-Štefin ◽

Boris Turk ◽

Nataša Kopitar-Jerala

Keyword(s):

Mouse Model ◽

Redox Homeostasis ◽

Underlying Mechanism ◽

Loss Of Function ◽

Altered Expression ◽

Lps Challenge ◽

Progressive Myoclonus Epilepsy ◽

Myoclonus Epilepsy ◽

The Brain ◽

Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

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