パーキンソン病

The Journal retracts the article "Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson's Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment" [...].

In-depth characterization of pathological protein aggregate with its subcomponents is pivotal for early diagnosis and staging of neurodegenerative disorders. Here, we introduce the Protein Aggregate NanoDynamics Analyzer (PANDA), a plasmonic nanotechnology-powered system that translates the supramolecular size distribution of protein aggregates into distinct scattering signatures via sterically constrained immunogold clustering. In this work, PANDA enabled the profiling of α-synuclein (α-syn) aggregates with diverse supramolecular architectures from human serum samples and experimentally revealed biological stage-dependent distribution patterns in Parkinson's disease (PD). Aggregate size profiles from PANDA readouts showed strong correlation with clinical scores (rmax = 0.6) and dopaminergic PET imaging (rmax = 0.7). Notably, it also confirmed the pathophysiological transition of "oligomer-to-fibril" in the course of PD progression. To leverage this transition, we incorporated a deep neural network (DNN) to classify PD stages. The network achieved high accuracy and enabled an objective reference to evaluate PD progression. PANDA system thus offers a noninvasive, artificial intelligence (AI)-augmented framework for molecular diagnosis and stratification of neurodegenerative diseases such as PD.

BACKGROUND: Parkinson's disease (PD) is predominantly characterized by unilateral motor manifestations and heterogeneous treatment responses. Combining single-pulse transcranial magnetic stimulation with electroencephalography (TMS-EEG) enables sensitive detection of cortical plasticity and dynamic brain network pathophysiology. METHODS: To elucidate the neural mechanisms underlying rehabilitation effects in PD, 27 left-affected (LPD) and 27 right-affected (RPD) patients were enrolled based on concordant lateralization between initial motor-symptom onset and current motor asymmetry quantified from the Movement Disorders Society-Sponsored Revised Unified Parkinson's Disease Rating Scale Part III limb subitems. All participants received a 2-week multidisciplinary intensive rehabilitation therapy (MIRT). By integrating single-pulse TMS-EEG recordings with adaptive directed transfer function analysis, this study evaluated network alterations within the primary motor cortex and posterior parietal cortex before and after MIRT. Furthermore, correlations between neural network changes and clinical functional improvements were examined. RESULTS: Significant alterations in brain network connectivity emerged, most notably 100 ms post-TMS of the posterior parietal cortex in the affected hemisphere. In LPD patients, decreased connectivity from the right central region to the parietal cortex correlated with improvements in axial symptoms, while increased outflow from the bilateral temporal lobes was associated with cognitive enhancement. Conversely, in RPD patients, decreased whole-brain transfer efficiency correlated with improved motor function, and changes in outflow from the left occipital and medial frontal lobes were associated with cognitive enhancement. CONCLUSION: The distinct modulatory effects of MIRT on the brain networks of LPD and RPD patients provide lateralized mechanistic insights into rehabilitation-related neural mechanisms in PD, potentially guiding the development of personalized and optimized therapeutic strategies.

Morin (3,5,7,2',4'-pentahydroxyflavone) is a dietary flavonol with broad neuroprotective, anti-inflammatory, and antioxidant actions across central and peripheral nervous system models. This synthesis consolidates evidence from in vitro and rodent studies-covering neurodegenerative proteinopathies (Alzheimer's, Parkinson's, and Huntington's), neuropathic pain, epilepsy, stress- and schizophrenia-like phenotypes, and chemo-/toxicant-induced neurotoxicity-to evaluate morin's consistent benefits on survival, motor/cognitive performance, and biochemical normalization. Morin mitigated neurotoxicity induced by doxorubicin, ifosfamide, vincristine, acrylamide, heavy metals, and endocrine disruptors. Context-specific effects included modulation of disease-defining pathways (GSK3β/CDK5, mTORC1, PARP, and AMPK-ULK1-TFEB), microglial polarization, and normalization of neurotransmission (dopamine, GABA, 5-HT, and reduced AChE). Core mechanisms included the following: restoration of redox and mitochondrial homeostasis via Nrf2/HO-1 activation; replenishment of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH); decreased reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO); and preserved mitochondrial potential/fusion; suppression of innate immune and inflammasome signaling through downregulation of TLR4/NF-κB and ERK-p65, reduced TNF-α, IL-1β/IL-6, iNOS/COX-2; inhibition of NLRP3/caspase-1; and rebalancing of cell-death programs (↓Bax/caspase-3, ↑Bcl-2; attenuation of RIPK1/RIPK3/MLKL-mediated necroptosis). Formulation strategies (intranasal microemulsions, pluronic micelles, and more soluble derivatives) have enhanced brain exposure and efficacy, but translation now warrants optimized delivery, pharmacokinetic-pharmacodynamic mapping, target engagement biomarkers, and rigorously controlled trials to define dose, route, and indications as adjunctive to standard care in neurodegeneration, neuropathic pain, and toxicant-related brain injury. Collectively, morin emerges as a multitarget neuroprotective scaffold with reproducible functional and mechanistic benefits.

The LRRK2 G2019S mutation, a Parkinson's disease-linked variant, has been associated with depression-like phenotypes, but mechanisms remain unclear. We chart age-dependent behavioral changes and astrocyte reactivity in G2019S mice and define a pathway connecting LRRK2 to TFEB/GDNF signaling, cellular energetics, and inflammation. From ∼25 weeks, G2019S carriers show robust depressive-like behaviors with reduced hippocampal GDNF, exaggerated astrocytic inflammation, diminished ATP, and increased neuronal apoptosis; pharmacologic LRRK2 kinase inhibition reverses these abnormalities. Single-cell transcriptomics identifies 507 differentially expressed genes enriched for adenylyl cyclase/cAMP signaling, oxidative phosphorylation/ATP metabolism, calcium/ion homeostasis, and cytokine pathways, indicating disrupted cAMP-ATP coupling and perturbed neuroimmune signaling. Mechanistically, LRRK2 G2019S binds and suppresses TFEB while elevating Ser211 phosphorylation, lowering astrocytic GDNF, amplifying inflammation, and reducing ATP. Critically, TFEB overexpression restores GDNF, elevates astrocytic ATP, attenuates inflammatory mediators, and improves depressive-like behaviors. Enhancing effector nodes is therapeutic: bilateral hippocampal forskolin rapidly (within 6 h) raises cAMP and reverses multiple behavioral measures, and ATP supplementation (systemic or hippocampal) yields comparable benefits. These findings position a LRRK2→TFEB/GDNF→cAMP/ATP axis as a driver of astrocytic inflammation and energetic imbalance underlying depression in G2019S mice and highlight convergent therapeutic strategies targeting LRRK2, TFEB, and ATP/cAMP.