Search Results (829)

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder in which oxidative stress represents a final common pathway linking diverse genetic and environmental insults to dopaminergic neuron loss. This review synthesizes evidence on how the commonly observed pathological changes in PD converge on excessive reactive oxygen species generation and redox imbalance. We present an overview on these pathways and key PD-linked genes that perturb mitochondrial quality control, lysosomal function, and inflammatory signaling, reinforcing oxidative stress. The major classes of redox-targeted therapeutic strategies under preclinical and clinical evaluation are outlined. Although many candidates show robust target engagement and neuroprotection in models, clinical trials have frequently yielded neutral or modest results, highlighting challenges related to brain delivery, off-target effects, optimal treatment window, and the fact that oxidative stress alone may be necessary but not sufficient to drive human disease progression. In the current paper, beyond cataloguing oxidative pathways, we explain the role of etiologic heterogeneity on biochemical target engagement and clinical outcomes. We outline subtype-enriched trial strategies and rational combination approaches. Targeting oxidative stress–related pathways thus remains a promising avenue for disease modification in PD, provided that future interventions are mechanistically informed and adapted to patient-specific redox vulnerabilities. Full article

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5–20% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G>A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development. Full article

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency, accumulation of globotriaosylceramide (Gb3), and progressive multiorgan involvement. Increasing evidence indicates that oxidative stress plays a central role in disease pathogenesis. This review aims to synthesize current knowledge on the molecular mechanisms underlying oxidative stress, the relevance of oxidative damage biomarkers, and potential therapeutic implications. A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar using terms related to Fabry disease, Gb3 metabolism, mitochondrial and endothelial dysfunction, inflammatory signaling, and oxidative stress markers. Clinical, experimental, and translational studies were included. Available data demonstrate that Gb3 accumulation disrupts mitochondrial function and activates NADPH oxidase, NF-κB, and MAPK signaling pathways, resulting in excessive production of reactive oxygen species. These processes contribute to cellular injury, particularly within the cardiovascular, renal, and nervous systems. Biomarkers such as malondialdehyde, 8-hydroxy-2′-deoxyguanosine, glutathione redox status, and antioxidant enzyme activities appear useful for assessing oxidative burden and monitoring therapeutic responses. Overall, current evidence underscores the pivotal role of oxidative stress in the progression of Fabry disease and highlights the need for further research into targeted antioxidant and disease-modifying therapeutic strategies. Full article

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, and disturbance of lysosomal degradation. Central to these processes is glutathione (GSH), a key antioxidant regulating redox balance and cellular homeostasis. This study aimed to evaluate the therapeutic potential of two dietary antioxidants—astaxanthin and Garcinia indica (kokum)—in modulating hepatic redox status, lysosomal function, and metabolic gene expression in a murine model of diet-induced NAFLD. A total of 120 male Swiss Webster mice were allocated into control and steatotic groups, followed by a 90-day supplementation period with astaxanthin, kokum, or their combination. Liver tissue was collected post-supplementation for biochemical, antioxidant, and qRT-PCR analyses. Outcomes included lysosomal enzymes activities, superoxide dismutase (SOD), GSH, vitamin C, total polyphenols, DPPH radical-scavenging activity, and total antioxidant capacity (TAC). NAFLD induced marked oxidative stress, lysosomal overactivation, and alteration of antioxidant-related gene expression. Combined supplementation restored GSH, enhanced TAC, reduced lysosomal stress markers, and significantly upregulated nuclear factor erythroid 2-related factor 2 (Nfe2l2) while downregulating fatty acid synthase (FASN) and partially rescuing lipoprotein lipase (LpL). Correlation analyses revealed strong associations between antioxidant capacity, lysosomal function, and transcriptional regulation, supporting the therapeutic relevance of combined antioxidant therapy for concurrent redox and lysosomal dysregulation in NAFLD. These findings underscore the therapeutic potential of targeting redox and cellular degradation pathways with antioxidant-based interventions to re-establish hepatic metabolic balance in NAFLD and related disorders. Full article

Neurodegenerative disorders are increasingly linked to a progressive decline in lysosomal function. Activating Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has therefore emerged as a promising therapeutic strategy to enhance cellular clearance in these conditions. In this study, we identified KHS-101 as a novel TFEB activator through a high-throughput screen of blood–brain-barrier-permeable small molecules. We demonstrated that KHS-101 promotes TFEB nuclear translocation, enhances lysosomal biogenesis and proteolytic activity, and increases autophagic flux. Furthermore, KHS-101 significantly accelerates the degradation of pathogenic A53T mutant α-synuclein in a cellular model of Parkinson’s disease, suggesting its potential to mitigate α-synuclein-mediated proteotoxicity and hold neuroprotective potential. Our findings identify KHS-101 as a potent TFEB activator and highlight the therapeutic potential of modulating the autophagy-lysosomal pathway for treating Parkinson’s disease and related disorders. Full article

Infantile-onset lysosomal acid lipase deficiency (LAL-D) (Wolman disease, historically) is a rare inherited, rapidly progressive disorder caused by pathogenic variants in the LIPA gene, which encodes the enzyme LAL. LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system. Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation. If untreated, rapidly progressive LAL-D typically leads to death within the first year of life. Treatment takes the two-pronged approach of sebelipase alfa, a human lysosomal acid lipase enzyme replacement therapy (ERT) that improves lipid metabolism, combined with nutritional management. Dietary substrate (lipid) reduction, known as substrate reduction therapy, is essential for optimal management in LAL-D. Following a nutritional plan and managing gastrointestinal disturbances together reduce systemic inflammation and improve growth, gut function, liver health, quality of life, and survival in patients with infantile-onset LAL-D. A multidisciplinary specialized team is necessary to manage the highly complex, multisystemic conditions in these patients. Nutritional management of LAL-D has evolved with increasing experience with the clinical management of ERT-treated infantile-onset LAL-D. A review of guidance for best practice nutritional management is needed. This narrative review aims to provide updated recommendations and guidance for the optimal nutritional management of infantile-onset LAL-D. Full article

Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome–mitochondria communication. Full article

Dysfunction of the membrane transporter P5B-ATPase 13A2 (ATP13A2) has been linked to neurodegenerative disorders, while its overexpression has been associated with colorectal cancer. ATP13A2 localizes to lysosomes and late endosomes, where it exports polyamines such as spermine into the cytosol. We previously showed that ATP13A2 expression alters lipid homeostasis and reduces the levels of bis(monoacylglycero)phosphate (BMP), an anionic phospholipid essential for lipid digestion in acidic compartments, suggesting that ATP13A2-mediated spermine export may affect lysosomal lipid catabolism. α/β-hydrolase domain-containing 6 (ABHD6), the enzyme responsible for BMP catabolism, was detected by immunofluorescence and immunoblot analysis in SH-SY5Y cells overexpressing human ATP13A2 and treated with spermine. The activities of the lipid-degrading hydrolases acid ceramidase (ACase) and glucocerebrosidase (GCase) were measured using specific fluorogenic substrates. ATP13A2-expressing cells showed higher ABHD6 expression, and spermine treatment promoted its translocation to the cytoplasm. Spermine induced a transient increase in ACase activity, followed by a stronger inhibition in ATP13A2-expressing cells. Moreover, GCase activity was elevated in these cells but also showed greater spermine-induced inhibition. Altogether, these results suggest that ATP13A2-mediated spermine export modulates the lipid digestion capacity of the endolysosomal system and support a functional interplay between polyamine and lipid metabolism in these organelles. Full article

The autophagy–lysosome system is a master regulator of cellular homeostasis, integrating quality control, metabolism, and cell fate through the selective degradation of cytoplasmic components. Disruption of either autophagic flux or lysosomal function compromises this degradative pathway and leads to diverse pathological conditions. Emerging evidence identifies the autophagy–lysosome network as a central signaling hub that connects metabolic balance to disease progression, particularly in neurodegenerative disorders and cancer. Although cancer and neurodegenerative diseases exhibit seemingly opposite outcomes—uncontrolled proliferation versus progressive neuronal loss—both share common mechanistic foundations within the autophagy–lysosome axis. Here, we synthesize recent advances on the roles of autophagy and lysosomal mechanisms in neurodegenerative diseases and cancer, especially on how defects in lysosomal acidification, membrane integrity, and autophagosome–lysosome fusion contribute to toxic protein accumulation and organelle damage in Alzheimer’s and Parkinson’s diseases, while the same machinery is repurposed by tumor cells to sustain anabolic growth, stress tolerance, and therapy resistance. We also highlight emerging lysosome-centered therapeutic approaches, including small molecules that induce lysosomal membrane permeabilization, nanomedicine-based pH correction, and next-generation protein degradation technologies. Finally, we discuss the major challenges and future opportunities for translating these mechanistic insights into clinical interventions. Full article

The disparity in outcomes between preclinical and clinical studies supplementing coenzyme Q10 (CoQ10) in neurological disorders may be a reflection of the differences in the ability of supplemental CoQ10 to access the blood–brain barrier (BBB) in rodents and in humans, which is, in turn, a consequence of contrasting structures of the BBB. The applicability of in vivo animal models to study access of CoQ10 across the BBB and subsequent neuronal metabolism has, therefore, been questioned, and there is an argument, perhaps surprisingly, that in vitro model systems (particularly 3D cellular systems) may be more appropriate. In this article, we have, therefore, reviewed the role of model systems to study the access of CoQ10 across the BBB, as well as the role of such systems in studying the role of CoQ10 in aspects of neuronal metabolism, such as mitochondrial and lysosomal function. In addition, the use of such model systems to study the interactions of CoQ10 with vitamin E and selenium has been reviewed. Finally, the practical application of a neuronal model system to investigate the effect of CoQ10 supplementation on CoQ10 status and mitochondrial metabolism in a CoQ10 deficiency state has been described. Full article

Background: Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by pathogenic variants in the HGSNAT gene. Data from large patient cohorts remain scarce, particularly in Latin America. Methods: We retrospectively analyzed clinical, biochemical, and genetic data from patients diagnosed with MPS IIIC through the MPS Brazil Network. Diagnosis was based on reduced activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), elevated urinary glycosaminoglycans (uGAGs), and/or molecular genetics tests. Results: A total of 101 patients were confirmed with MPS IIIC, representing one of the largest cohorts worldwide. Females accounted for 60% of cases. The mean age at symptom onset was 5.4 ± 3.9 years, while the mean age at diagnosis was 11.7 ± 6.9 years, reflecting a 6-year diagnostic delay. Most patients initially presented with developmental delay (82%) and facial dysmorphism (80%), whereas behavioral manifestations were less frequently identified (25%), suggesting a milder phenotype than previously reported. Genetic information was available for 28% of patients, showing recurrent alleles (c.372-2A>G, c.252dupT) and several novel mutations, which expand the mutational spectrum of the disease. Genotype–phenotype similarities with Portuguese, Italian, and Chinese cases suggest shared ancestry contributions. Regional differences included earlier diagnoses in the North of Brazil and high consanguinity rates in the Northeast region. Conclusions: This study describes the largest Brazilian cohort of MPS IIIC, documenting novel variants and regional heterogeneity. Findings highlight diagnostic delays, ancestry influences, and the urgent need for disease-modifying therapies. Full article

Fabry disease (FD) is an X-linked lysosomal disorder caused by GLA mutations, typically associated with glycosphingolipid accumulation and a wide phenotypic spectrum. The p.R112H variant is generally linked to a non-classic predominantly renal phenotype with mild biochemical abnormalities and slow progression. We report the case of a young woman carrying the R112H mutation who exhibited early-onset kidney involvement and unusually rapid progression to end-stage renal disease. Clinical history, serial evaluations, and kidney biopsy findings initially supported a diagnosis of Fabry nephropathy; however, re-evaluation of the native kidney biopsy revealed marked remodeling and multilamellation of the glomerular basement membrane, suggesting Alport-like lesions. Subsequent genetic testing confirmed a heterozygous pathogenic COL4A4 variant (G912R), indicating coexistence of Fabry disease and autosomal dominant Alport syndrome. This dual genetic condition likely accounted for the accelerated decline in kidney function, in contrast with the typically mild phenotype associated with R112H. Our literature review indicates that coexistence of these two inherited nephropathies has not previously been confirmed either histologically or genetically. This case underscores the importance of integrating genetic and ultrastructural assessment in patients with atypical or rapidly progressive renal disease Full article

Neurometabolic diseases encompass a diverse group of rare and often progressive genetic disorders affecting the nervous system due to abnormalities in metabolic pathways. These conditions, including mitochondrial disorders, lysosomal storage diseases, and others, can manifest in adults with a range of neurological symptoms, which will be reviewed here. Given their complexity and chronic nature, comprehensive management is crucial for improving patients’ quality of life. In this Invited Perspective, we review the neurological signs and symptoms of the most commonly encountered inherited metabolic disorders in adult neurology. Furthermore, drawing on our clinical experience, we demonstrate that an integrated local care approach is fundamental for these patients, as it enables continuous monitoring, early intervention, and coordinated multidisciplinary support. Full article

Lysosomal storage disorders (LSDs) are a group of rare inherited diseases caused by mutations in the genes encoding the proteins involved in normal lysosomal functions, leading to an accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. The development of powerful and reliable animal model systems that can in vivo recapitulate human LSD pathologies is critical for understanding disease mechanisms and advancing therapeutic strategies. In this study, we identified the Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain–midgut axis via the use of GAL4/UAS and RNAi combined technologies. Transgenic fly models presented key features of human LSD pathologies, including significantly shortened lifespans and a progressive locomotor decline that serves as a measure for neuromuscular disintegration, following age- and sex-dependent patterns. These phenotypic parallels in pathology strongly support the functional relevance of the selected orthologs and underscore the value of Drosophila as a versatile in vivo model system for advanced LSD pathology research, offering state-of-the-art genetic tools for molecularly dissecting disease mechanisms and providing cutting-edge novel platforms for high-throughput genetic and/or pharmacological screening, moving towards development of new therapeutically beneficial drug-based regimens and mutant gene-rescue schemes. Full article

Background/Objectives: Krabbe disease (KD) is a hereditary lysosomal disorder whose hallmark is progressive demyelination, with variable involvement of the central nervous system. It is caused by pathogenic variants in the GALC gene that disrupt the function of its gene product, the lysosomal enzyme galactosylceramidase. We analyzed two unrelated cases (one early infantile and one adult) with a clinical suspicion of KD. Methods: We used a combination of biochemical techniques (high-performance liquid chromatography–tandem mass spectrometry), NGS (resequencing gene panels), splicing assays, and molecular modeling to identify and analyze the pathogenicity of the variants underlying the disorder. Results: The two probands were compound heterozygotes for disease-causing variants in the GALC gene, encoding the lysosomal hydrolase galactosylceramidase. Three of the variants were novel and caused aberrant splicing, either by exon skipping (c.908+5G>A and c.1034-1G>C) or by inclusion of a cryptic, deep intronic pseudoexon (c.621+772G>C). The fourth variant was a known missense change (c.956A>G, p.(Tyr319Cys)) with conflicting interpretations of pathogenicity in the databases. Conclusions: We demonstrated the pathogenicity of the three novel splicing variants, all with strong impact on galactosylceramidase function. We also concluded that the c.956A>G missense variant is a hypomorph usually underlying the later-onset, milder phenotypes of KD. Our results stress the importance of integrated approaches combining clinical, biochemical, and genetic testing to obtain a definitive diagnosis of lysosomal diseases. Full article