4 research outputs found
A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN
Neurodegenerative Disorders: Spotlight on Sphingolipids
Neurodegenerative diseases are incurable diseases of the nervous system that lead to a progressive loss of brain areas and neuronal subtypes, which is associated with an increase in symptoms that can be linked to the affected brain areas. The key findings that appear in many neurodegenerative diseases are deposits of proteins and the damage of mitochondria, which mainly affect energy production and mitophagy. Several causative gene mutations have been identified in various neurodegenerative diseases; however, a large proportion are considered sporadic. In the last decade, studies linking lipids, and in particular sphingolipids, to neurodegenerative diseases have shown the importance of these sphingolipids in the underlying pathogenesis. Sphingolipids are bioactive lipids consisting of a sphingoid base linked to a fatty acid and a hydrophilic head group. They are involved in various cellular processes, such as cell growth, apoptosis, and autophagy, and are an essential component of the brain. In this review, we will cover key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases and will focus on neurodegeneration with brain iron accumulation and Parkinson’s disease
DataSheet1_A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities.docx
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN.</p
Presentation1_A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities.PPTX
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN.</p