Targeting Gys1 with AAV‐SaCas9 Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models

Gumusgoz, Emrah; Guisso, Dikran R; Kasiri, Sahba; Wu, Jun; Dear, Matthew; Verhalen, Brandy; Nitschke, Silvia; Mitra, Sharmistha; Nitschké, Felix; Minassian, Berge A.

doi:10.1007/s13311-021-01040-7

Cited by 34 publications

(38 citation statements)

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“…This was confirmed in LD mouse models. Down-regulating GS was achieved with (1) crosses between LD models and mice deficient of GS or proteins that activate this enzyme [87][88][89][90]; (2) delivering Gys1 targeting CRISPR/Cas9 to the brain with AAV9 [91] and (3) antisense oligonucleotides (ASO) against GS gene [92]. In all cases, PBs were drastically reduced and consequent neuropathological and behavioral phenotypes improved.…”

Section: Glycogen Synthase Reduction Therapymentioning

confidence: 99%

LUBAC: a new player in polyglucosan body disease

Aboujaoude

Minassian

Mitra

2021

Biochemical Society Transactions

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Altered protein ubiquitination is associated with the pathobiology of numerous diseases; however, its involvement in glycogen metabolism and associated polyglucosan body (PB) disease has not been investigated in depth. In PB disease, excessively long and less branched glycogen chains (polyglucosan bodies, PBs) are formed, which precipitate in different tissues causing myopathy, cardiomyopathy and/or neurodegeneration. Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex composed of two E3 ubiquitin ligases HOIL-1L and HOIP and an adaptor protein SHARPIN. Together they are responsible for M1-linked ubiquitination of substrates primarily related to immune signaling and cell death pathways. Consequently, severe immunodeficiency is a hallmark of many LUBAC deficient patients. Remarkably, all HOIL-1L deficient patients exhibit accumulation of PBs in different organs especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC's important role in glycogen metabolism. To date, neither a glycogen metabolism-related LUBAC substrate nor the molecular mechanism are known. Hence, current reviews on LUBAC's involvement in glycogen metabolism are lacking. Here, we aim to fill this gap by describing LUBAC's involvement in PB disease. We present a comprehensive review of LUBAC structure, its role in M1-linked and other types of atypical ubiquitination, PB pathology in human patients and findings in new mouse models to study the disease. We conclude the review with recent drug developments and near-future gene-based therapeutic approaches to treat LUBAC related PB disease.

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Section: Glycogen Synthase Reduction Therapymentioning

confidence: 99%

LUBAC: a new player in polyglucosan body disease

Aboujaoude

Minassian

Mitra

2021

Biochemical Society Transactions

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“…Several recent articles explore possible therapies for LD based on replacing the missing genes, inhibiting glycogen synthesis or introducing enzymes that can digest LBs [18,[59][60][61][62]. Moreover, beyond LD, we have witnessed an increasing body of literature showing glycogen accumulation as a new common thread in aging, neurodegenerative diseases (including Alzheimer's, Parkinson's and Huntington's disease and amyotrophic lateral sclerosis [63][64][65]) and epilepsy [18,[66][67][68][69].…”

Section: Discussionmentioning

confidence: 99%

Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora

et al. 2021

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Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

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“…Gene therapy has delivered promising results in animal experimental models, raising the hopes that it might soon become available for patients. CRISPR/Cas9 biotechnology holds great promise in neurological therapy, pending the clearance of major delivery, efficiency and specificity hurdles 153 …”

Section: Aetiology‐based Preventive and In Progress Treatments (Table 3)mentioning

confidence: 99%

“…CRISPR/Cas9 biotechnology holds great promise in neurological therapy, pending the clearance of major delivery, efficiency and specificity hurdles. 153…”

Section: Aetiology-based Preventive and In Progress Treatments (Table 3)mentioning

confidence: 99%

Novel treatments in epilepsy guided by genetic diagnosis

Marini¹,

Giardino²

2021

Brit J Clinical Pharma

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In recent years, precision medicine has emerged as a new paradigm for improved and more individualized patient care. Its key objective is to provide the right treatment, to the right patient at the right time, by basing medical decisions on individual characteristics, including specific genetic biomarkers. In order to realize this objective researchers and physicians must first identify the underlying genetic cause; over the last 10 years, advances in genetics have made this possible for several monogenic epilepsies. Through next generation techniques, a precise genetic aetiology is attainable in 30–50% of genetic epilepsies beginning in the paediatric age. While committed in such search for novel genes carrying disease‐causing variants, progress in the study of experimental models of epilepsy has also provided a better understanding of the mechanisms underlying the condition. Such advances are already being translated into improving care, management and treatment of some patients. Identification of a precise genetic aetiology can already direct physicians to prescribe treatments correcting specific metabolic defects, avoid antiseizure medicines that might aggravate functional consequences of the disease‐causing variant or select the drugs that counteract the underlying, genetically determined, functional disturbance. Personalized, tailored treatments should not just focus on how to stop seizures but possibly prevent their onset and cure the disorder, often consisting of seizures and its comorbidities including cognitive, motor and behaviour deficiencies. This review discusses the therapeutic implications following a specific genetic diagnosis and the correlation between genetic findings, pathophysiological mechanisms and tailored seizure treatment, emphasizing the impact on current clinical practice.

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Targeting Gys1 with AAV‐SaCas9 Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models

Cited by 34 publications

References 50 publications

LUBAC: a new player in polyglucosan body disease

LUBAC: a new player in polyglucosan body disease

Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora

Novel treatments in epilepsy guided by genetic diagnosis

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