title: Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases.
abstract: Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review.
authors.affiliation: 1] Division of Inherited Metabolic Diseases, Department of General Pediatrics, Heidelberg Children's Hospital, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany [2] Institute of Anatomy and Cell Biology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Ebrahimi-Fakhari
authors.affiliation: 1] Division of Inherited Metabolic Diseases, Department of General Pediatrics, Heidelberg Children's Hospital, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany [2] Institute of Physiology and Pathophysiology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Wahlster
authors.affiliation: Division of Inherited Metabolic Diseases, Department of General Pediatrics, Heidelberg Children's Hospital, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Division of Inherited Metabolic Diseases, Department of General Pediatrics, Heidelberg Children's Hospital, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
mesh_terms: D000367:Age Factors; D061085:Agenesis of Corpus Callosum / Q000378:metabolism / Q000473:pathology; D038261:Alexander Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001928:Brain Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D002386:Cataract / Q000378:metabolism / Q000473:pathology; D002648:Child; D004734:Energy Metabolism / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D020192:Lafora Disease / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D012307:Risk Factors