We aimed to compare the effect of transcranial direct current stimulation (tDCS) compared with sham or conventional interventions on motor functions and activity in individuals with Parkinson's disease. Two independent reviewers searched four databases (PubMed, Embase, Scopus, and Cochrane Library) from inception to April 2026. We only included randomized controlled trials comparing active tDCS (alone or with training) versus sham tDCS (alone or with training) on walking speed, functional mobility, Parkinson motor symptoms, activities of daily living, quality of life (QoL), dropouts, and adverse events. Two authors independently extracted data, including study source and design, participant and intervention characteristics, and outcomes. We computed a mean difference with a random-effects model. Subgroup analyses were performed for outcomes with greater than or equal to 10 experimental study arms, accounting for intervention protocol and stimulation site. We assessed the risk of bias using ROB 2 tool, and the certainty of evidence using Grading of Recommendations Assessment, Development, and Evaluation. Seventeen randomized controlled trials (n = 553) were included. Pooled analyses showed little to no effect on walking speed (mean difference: 0.04 m/s2, 95% confidence interval: -0.03 to 0.11), functional mobility (mean difference: 0.67 s gained on the Timed Up and Go test, 95% confidence interval: -0.64 to 2.02), and other outcomes. Subgroup analyses based on stimulation site and intervention protocol revealed no differences. Adverse events were minor and infrequent, and dropout rates did not differ between groups. The overall certainty of evidence ranged from very low to low. Current evidence suggests that the effect of tDCS on gait, activities of daily living, or quality of life is probably not superior to other conventional interventions in individuals with Parkinson's disease.

Superoxide (O2-), generated by mitochondrial respiration and redox enzymes, may act as a cellular ageing trigger (CAT) when dysregulated. This study investigated whether mitochondrial (rotenone-induced) and cytoplasmic (paraquat-induced) O2- imbalance produces similar or distinct oxi-inflammatory activation in human peripheral blood mononuclear cells (PBMCs). Two in vitro protocols were performed. First, PBMCs were exposed to rotenone (ROT) or paraquat (PQT) for 6 or 24 h, using phytohaemagglutinin (PHA) as a positive control. Second, 48-h cultures from 21 donors, including healthy controls (HC) and individuals with Parkinson's disease (PD), were treated with 30 μM ROT or PQT. Cell viability was evaluated by the MTT assay (metabolic activity) and trypan blue exclusion (membrane integrity). Cytokines, O2-, nitric oxide (NO) and morphometric parameters were quantified. ROT and PQT induced distinct early responses: ROT increased IL-1β and NO, whereas PQT caused delayed elevations of IL-1β, O2- and NO. Because no baseline differences were detected between HC and PD donors, data were analysed jointly. After 48 h, both oxidants elevated IL-1β, IL-6, TNF-α and NO. Morphometric analysis revealed ROT-associated fragmentation and PQT-induced hyperchromatic aggregates, consistent with pro-inflammatory damage-associated molecular patterns (DAMPs). These findings indicate that mitochondrial and cytoplasmic O2- imbalance initiates oxi-inflammatory activation in PBMCs, supporting superoxide dysregulation as a potential CAT and a hormetic modulator of ageing-related signalling.

COVID-19 is mainly associated with respiratory symptoms, although several reports show that SARS-CoV-2 affects the nervous system. We evaluated the effects of SARS-CoV-2 infection on human derived midbrain organoids by exposing them to the virus (multiplicity of infection 0.05, 16-h exposure) and analyzing cellular and molecular changes at 4 and 28 days post-infection using immunofluorescence microscopy and RNA sequencing. SARS-CoV-2 nucleocapsid protein preferentially colocalized with tyrosine hydroxylase-positive (TH+) dopaminergic neurons, inducing neurite fragmentation and cellular stress. Transcriptomic analysis revealed dysregulation of pathways related to cell stress and death, DNA damage response, neurodevelopment, and neuronal survival at both timepoints. Persistent alterations in vesicle trafficking, Notch signaling, and mitochondrial function were observed at 28 days post-infection. Analysis of non-coding RNA expression highlighted dysregulated genomic regions associated with viral replication and neurite growth. These findings demonstrate selective vulnerability of dopaminergic neurons to SARS-CoV-2 infection with persistent molecular alterations, providing mechanistic insights into potential neurological consequences of COVID-19.

Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.

Ischemic stroke remains a leading cause of global mortality and long-term disability, driven largely by oxidative stress, mitochondrial dysfunction, and inflammatory cascades. DJ-1 (PARK7), a redox-sensitive protein originally implicated in Parkinson's disease, has emerged as a critical neuroprotective regulator in cerebral ischemia. Oxidation of its cysteine-106 residue enables DJ-1 to stabilize mitochondrial function, suppress reactive oxygen species, and activate Nrf2-dependent antioxidant defenses. DJ-1 deficiency markedly exacerbates infarct size and neuronal vulnerability, whereas its activation confers robust neuroprotection. This review highlights DJ-1 as a promising redox-responsive therapeutic target for limiting ischemic brain injury.

Advanced-stage Parkinson's disease (PD) and myasthenia gravis (MG) share overlapping clinical features, including dysphagia, dysarthria, fatigue, and fluctuating symptoms. When PD precedes MG, these manifestations may be misinterpreted as a progression of PD, potentially leading to an underdiagnosis of MG. Although the coexistence of PD and MG is rare, it nevertheless requires careful consideration. Furthermore, the pharmacological treatments for these two disorders differ substantially, and medications used for one condition may exacerbate the other condition. We report a patient with PD complicated by MG, in whom anticholinergic treatment with biperiden led to the exacerbation of MG-related symptoms, ultimately resulting in the diagnosis of MG.

Beta-propeller protein-associated neurodegeneration (BPAN) is a neurodegeneration with brain iron accumulation (NBIA) disorder caused by autophagy abnormalities. Clinical features of BPAN include global developmental delay in early childhood, followed by progression of cognitive dysfunction and parkinsonism in adulthood. A 32-year-old woman diagnosed with BPAN and confirmed by genetic analysis showed motor symptoms that rapidly progressed after the age of 30 years. Baclofen was administered for spasticity, though a high fever and elevated serum CK level were observed, and the symptoms persisted for several months even after stopping the drug. It was suspected that rhabdomyolysis have been due to muscle tissue fragility associated with autophagy impairment in BPAN, in combination with increased muscle tone.

Parkinson's disease (PD) is the second most common neurodegenerative disease, in which mitochondrial dysfunction and abnormal aggregation of alpha-synuclein (α-syn) play key roles in the pathology of PD. As a classic tumor suppressor, p53 has also been found to be involved in the pathological process of PD in recent years. However, the specific mechanism by which p53 regulates mitochondrial function and abnormal aggregation of α-syn is still unclear. Here, we observed that the expression of α-syn and p53 was increased and mitochondria were impaired in the MPTP-induced PD mouse model, leading us to propose speculation on whether p53 affects mitochondrial impairment and abnormal α-syn aggregation in PD pathology. Next, cellular experiments revealed that the p53 inhibition by pifithrin-α regulates mitochondrial function through mitophagy and mitochondrial dynamics, then ameliorates oxidative stress and apoptosis in PD. Meanwhile, the in vitro study showed that the p53 protein interacted with α-syn to accelerate the process of α-syn liquid-liquid phase separation and amyloid fibril formation, promoting the development of PD pathology. In summary, p53 modulates mitochondrial function through mitophagy and mitochondrial dynamics, stimulating the pathogenic aggregation of α-syn protein and neurodegeneration in Parkinson's disease.