脳内鉄沈着神経変性症

Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Perioperative neurocognitive disorders (PND) are common neurological complications in elderly surgical patients, for which effective mechanism-based therapies remain lacking. This study identifies ferroptosis, an iron-dependent lipid peroxidation-driven cell death, as a key pathological process in PND, and pharmacological inhibition of ferroptosis with ferrostatin-1 significantly ameliorated cognitive deficits in a surgery and anesthesia-induced mouse model of PND. Moreover, accumulation of glutamate has been observed in the brains of PND mice, which competitively inhibits the neuronal cystine/glutamate antiporter system Xc- (via SLC7A11) to trigger glutathione depletion and ferroptotic cell death. Excessive glutamate production and release are driven by hyperexpression of glutamate-producing enzyme glutaminase 1 (GLS1) in activated microglia via STAT1-dependent transcriptional activation. Pharmacological inhibition of GLS1 with the selective inhibitors CB839 and BPTES suppressed ferroptosis, preserved synaptic plasticity, and improved cognitive performance in PND mice, indicating GLS1 as a potential therapeutic target of PND. Notably, elevated plasma GLS1 levels in PND patients correlated negatively with cognitive test scores (R2 = 0.479, p < 0.001) and exhibited moderate diagnostic value across two independent cohorts (AUCs = 0.77 and 0.84), underscoring its clinical relevance as a potential biomarker. Collectively, our findings establish microglial GLS1 as a critical mediator of ferroptosis in PND and highlight its dual promise as a therapeutic target and diagnostic indicator.

Pantothenate kinase-associated neurodegeneration (PKAN) is the most common form of neurodegeneration with brain iron accumulation (NBIA), typically characterized by extrapyramidal symptoms and the classical eye-of-the-tiger sign on MRI. However, atypical forms may lack this hallmark feature, leading to diagnostic challenges. We report a 27-year-old male with a 12-year history of progressive tremors, gait disturbance, dysarthria, dysphagia, and behavioral changes. Neurological examination revealed extrapyramidal features, including dystonia and sialorrhea. MRI brain demonstrated bilateral T2 hypointensity in the globus pallidus with prominent blooming on susceptibility-weighted imaging (SWI), suggestive of iron deposition, without the classical eye-of-the-tiger sign. A diagnosis of clinically suspected atypical PKAN was made based on the characteristic clinical and radiological findings, and genetic confirmation by PANK2 mutation testing was advised. Atypical PKAN often presents later with slower progression and may lack characteristic MRI findings. This case highlights the diagnostic limitations of conventional MRI and emphasizes the importance of SWI in detecting basal ganglia iron deposition. PKAN should be considered in young patients with progressive extrapyramidal symptoms even in the absence of the eye-of-the-tiger sign. SWI can improve diagnostic accuracy and help reduce delays in diagnosis.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and excitotoxicity. Ferroptosis and N-methyl-D-aspartate (NMDA) receptor activity,may be interconnected in the pathogenesis of Aβ accumulation and associated neurodegeneration in AD. However, the interplay between these pathways remains poorly understood and underexplored for therapeutic intervention against the AD. The review aims to explore the shared molecular triggers of ferroptosis and NMDA receptor overactivation, including the roles of iron, glutamate overload, calcium dysregulation, and reactive oxygen species (ROS) accumulation. We further highlighted the convergent consequences of these processes on mitochondrial dysfunction, lipid peroxidation, and their impact on Aβ pathology. Particular attention is given to P-glycoprotein (P-gp), an efflux transporter involved in the Aβ clearance at the blood-brain barrier, whose expression and function may be modulated by oxidative stress, iron homeostasis, and NMDA receptor signaling. Emerging evidence indicated that ferroptosis and NMDA receptor activity may disrupt P-gp function, thereby impairing Aβ clearance and promoting its accumulation in the AD. Overall, the review elucidates the molecular mechanisms linking ferroptosis and NMDA receptor overactivation and their impact on P-gp-mediated Aβ transport in the AD, providing integrated mechanisms and harnessing their potential for AD therapeutics.

Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically heterogeneous group of rare movement disorders characterized by progressive neurodegeneration and selective basal ganglia iron deposition. Recent discoveries have fundamentally reshaped the understanding of NBIA, indicating that defects in coenzyme A metabolism, mitochondrial bioenergetics, lipid remodeling, autophagy-lysosomal pathways, and ferroptosis precede and promote secondary iron dyshomeostasis rather than resulting from primary abnormalities in iron metabolism. This review integrates recent mechanistic and translational evidence (2020-2026) across both common and underrepresented NBIA subtypes, including pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, COASY protein-associated neurodegeneration, mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, mitochondrial membrane protein-associated neurodegeneration, β-propeller protein-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, neuroferritinopathy, and mitochondrial DNA-associated forms. Unlike previous reviews, this synthesis consolidates findings from patient-derived induced pluripotent stem cell neuronal and glial models, compartment-specific iron localization, advanced neuroimaging biomarkers, and emerging therapeutic strategies within a unified mechanistic framework. Collectively, the evidence supports a paradigm in which mitochondrial dysfunction and lipid metabolic failure initiate disease progression, whereas iron accumulation amplifies oxidative injury and lipid peroxidation, thereby increasing ferroptotic cell death and neuronal degeneration, providing an updated foundation for biomarker discovery, mechanistically informed therapeutic development, and precision medicine approaches in NBIA.