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Publications

by Keyword: Neuroinflammation

Varea, Olga, Guinovart, Joan J, Duran, Jordi, (2022). Malin restoration as proof of concept for gene therapy for Lafora disease Brain Commun 4, fcac168

Abstract Lafora disease is a fatal neurodegenerative childhood dementia caused by loss-of-function mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of abnormal glycogen aggregates known as Lafora bodies (LBs) in the brain and other tissues. These aggregates are responsible for the pathological features of the disease. As a monogenic disorder, Lafora disease is a good candidate for gene therapy-based approaches. However, most patients are diagnosed after the appearance of the first symptoms and thus when LBs are already present in the brain. In this context, it was not clear whether the restoration of a normal copy of the defective gene (either laforin or malin) would prove effective. Here we evaluated the effect of restoring malin in a malin-deficient mouse model of Lafora disease as a proof of concept for gene replacement therapy. To this end, we generated a malin-deficient mouse in which malin expression can be induced at a certain time. Our results reveal that malin restoration at an advanced stage of the disease arrests the accumulation of LBs in brain and muscle, induces the degradation of laforin and glycogen synthase bound to the aggregates, and ameliorates neuroinflammation. These results identify malin restoration as the first therapeutic strategy to show effectiveness when applied at advanced stages of Lafora disease.

JTD Keywords: accumulation, gene therapy, glycogen, lafora disease, neurodegeneration, neuroinflammation, neurons, targets, Carbohydrate-binding domain, Glycogen


Pellegrini P, Hervera A, Varea O, Brewer MK, López-Soldado I, Guitart A, Aguilera M, Prats N, del Río JA, Guinovart JJ, Duran J, (2022). Lack of p62 Impairs Glycogen Aggregation and Exacerbates Pathology in a Mouse Model of Myoclonic Epilepsy of Lafora Molecular Neurobiology 59, 1214-1229

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. © 2021, The Author(s).

JTD Keywords: accumulation, astrocytes, autophagy receptors, contributes, deficient mice, epilepsy, glycogen, lafora bodies, lafora disease, malin, metabolism, neurodegeneration, neuroinflammation, p62, polyglucosan bodies, temporal-lobe epilepsy, Epilepsy, Glycogen, Inclusion-body formation, Lafora bodies, Lafora disease, Malin, Neuroinflammation, P62


Duran, J, Hervera, A, Markussen, KH, Varea, O, Lopez-Soldado, I, Sun, RC, del Rio, JA, Gentry, MS, Guinovart, JJ, (2021). Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease Brain 144, 2349-2360

The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malin(KO)). Strikingly, blocking glycogen synthesis in astrocytes-thus impeding Lafora bodies accumulation in this cell type-prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malin(KO) model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

JTD Keywords: Bodies, Deficient mice, Epilepsy, Glycogen, Impairment, Lafora disease, Malin, Modulation, Mouse model, Neurodegeneration, Neuroinflammation, Neurons, Progressive myoclonus epilepsy, Seizure susceptibility, Synthase


Mesquida-Veny F, Del Río JA, Hervera A, (2021). Macrophagic and microglial complexity after neuronal injury Progress In Neurobiology 200

© 2020 Elsevier Ltd Central nervous system (CNS) injuries do not heal properly in contrast to normal tissue repair, in which functional recovery typically occurs. The reason for this dichotomy in wound repair is explained in part by macrophage and microglial malfunction, affecting both the extrinsic and intrinsic barriers to appropriate axonal regeneration. In normal healing tissue, macrophages promote the repair of injured tissue by regulating transitions through different phases of the healing response. In contrast, inflammation dominates the outcome of CNS injury, often leading to secondary damage. Therefore, an understanding of the molecular mechanisms underlying this dichotomy is critical to advance in neuronal repair therapies. Recent studies highlight the plasticity and complexity of macrophages and microglia beyond the classical view of the M1/M2 polarization paradigm. This plasticity represents an in vivo continuous spectrum of phenotypes with overlapping functions and markers. Moreover, macrophage and microglial plasticity affect many events essential for neuronal regeneration after injury, such as myelin and cell debris clearance, inflammation, release of cytokines, and trophic factors, affecting both intrinsic neuronal properties and extracellular matrix deposition. Until recently, this complexity was overlooked in the translation of therapies modulating these responses for the treatment of neuronal injuries. However, recent studies have shed important light on the underlying molecular mechanisms of this complexity and its transitions and effects on regenerative events. Here we review the complexity of macrophages and microglia after neuronal injury and their roles in regeneration, as well as the underlying molecular mechanisms, and we discuss current challenges and future opportunities for treatment.

JTD Keywords: chemokines and cytokines, macrophages, microglia, neuroinflammation, neuronal injury, regeneration, Chemokines and cytokines, Macrophages, Microglia, Neuroinflammation, Neuronal injury, Regeneration