by Keyword: deficient mice
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
