title: Dysfunctions in endosomal-lysosomal and autophagy pathways underlie neuropathology in a mouse model for Lafora disease.
abstract: Lafora progressive myoclonus epilepsy (also known as Lafora disease, LD) is an inherited and fatal form of a neurodegenerative disorder characterized by the presence of carbohydrate-rich inclusions called Lafora bodies. LD can be caused by defects in the laforin phosphatase or the malin ubiquitin ligase and the clinical symptoms resulting from these two defects are almost similar. In order to understand the molecular basis of LD pathogenesis and the role of Lafora bodies in neuropathology, we have studied the laforin-deficient mice as a model and show here that Lafora bodies recruit proteasomal subunit, endoplasmic reticulum chaperone GRP78/Bip, autophagic protein p62 and endosomal regulators Rab5 and Rab7. The laforin-deficient brain also reveals the proliferation of enlarged lysosomes, lipofuscin granules, amyloid-β peptides and increased levels of insoluble form of ubiquitinated protein, indicating a significant impairment in the cellular degradative pathway. Further, abnormal dendrites and increased gliosis, especially at the vicinity of Lafora bodies, were noted in the LD brain. Taken together, our study suggests that the neuropathology in LD is not limited to Lafora bodies, that some of the neuropathological changes in LD are likely to be secondary effects caused by Lafora bodies, and that impairment in the autophagy-endosomal-lysosomal pathways might underlie some of the symptoms in LD.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
authors.forename: Rajat
authors.initials: R
authors.lastname: Puri
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D011992:Endosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D020192:Lafora Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054558:Protein Tyrosine Phosphatases, Non-Receptor
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor