Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect

FBXO7 is implicated in the ubiquitin–proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient’s fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.Fundacio La Marato de TV3 [Grants 20143130 to BPD, and 20143131 to CE], by the Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion within the framework of the National R + D+I Plan cofunded with ERDF funds [Grants PI18/01319 to BPD and PI18/00147 to CE], and by the Generalitat Valenciana [Grant PROMETEO/2018/ 135 to CE]. Part of the equipment employed in this work has been funded by Generalitat Valenciana and cofinanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). SFR had a contract funded by the Spanish Foundation Per Amor a l’Art (FPAA). PS had a FPU-PhD fellowship funded by the Spanish Ministry of Education, Culture and Sport Inmunoterapia

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect

Altres ajuts: This work was funded by Instituto de Salud Carlos III; Ministerio de Educación, Cultura y Deporte; Spanish Foundation per Amor a l'Art (FPAA) grant ; Fundació la Marató de TV3 grants 20143130; and 20143131; Generalitat Valenciana grants OP ERDF of Comunitat Valenciana 2014-2020; and PROMETEO/2018/135.FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders

Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology

Mutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.The authors wish to thank Dr. Arango (VHIR) for the PX461 vector and all the Vila lab members for their support. This work was supported by the Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (Spain)-FEDER (PI17/00496 and PI20/00728), the Michael J. Fox Foundation, the Silverstein Foundation (MJFF 16182), and the BBVA Foundation (NanoERT). M.M. was supported by an FPU doctoral fellowship (FPU18/05595) from MINECO (Spain); J.R. was supported by a PERIS fellowship (Generalitat de Catalunya); E.P. was supported by a VHIR doctoral fellowship (VHIR, Barcelona).Peer reviewe

The Emerging Role of the Lysosome in Parkinson's Disease

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson's disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson's disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop P

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect

Altres ajuts: This work was funded by Instituto de Salud Carlos III; Ministerio de Educación, Cultura y Deporte; Spanish Foundation per Amor a l'Art (FPAA) grant ; Fundació la Marató de TV3 grants 20143130; and 20143131; Generalitat Valenciana grants OP ERDF of Comunitat Valenciana 2014-2020; and PROMETEO/2018/135.FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders