by Keyword: Autophagy

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

Sánchez-Danés, A., Richaud-Patin, Y., Carballo-Carbajal, I., Jiménez-Delgado, S., Caig, C., Mora, S., Di Guglielmo, C., Ezquerra, M., Patel, B., Giralt, A., Canals, J. M., Memo, M., Alberch, J., López-Barneo, J., Vila, M., Cuervo, A. M., Tolosa, E., Consiglio, A., Raya, A., (2012). Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease EMBO Molecular Medicine 4, (5), 380-395

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.

JTD Keywords: Autophagy, Disease modeling, LRRK2 mutation, Neurodegeneration, Pluripotent stem cells