Search Results (53)

Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease—the major protagonists of NDs—while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials. Full article

Background and Objectives: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. Methods: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34–PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. Results: Twelve studies met the criteria across tauopathies and Alzheimer’s disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington’s disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer’s hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1–2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. Conclusions: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation. Full article

Background/Objectives: The voltage-gated potassium channels of the Kv4 family (Kv4.1, Kv4.2, Kv4.3) regulate neuronal excitability and synaptic integration. The dysregulation of these channels has been linked to neurodegenerative diseases, such as Alzheimer’s disease (AD), spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), prion diseases, and Parkinson’s disease (PD). Current evidence is scattered across diverse models, and a systematic synthesis is lacking. This review seeks to compile and analyze data on Kv4 channel alterations in neurodegeneration, focusing on genetic variants, functional changes, and phenotypic consequences. Methods: A systematic search was conducted for peer-reviewed studies, including human participants, human-derived cell models, and relevant animal models. Studies were considered eligible if they investigated Kv4.1–Kv4.3 (encoded by gene encoding the Kv4.1-Kv4.3 α-subunit of voltage-gated A-type potassium channels (KCND1-KCND3)) expression, function, or genetic variants, as well as associated auxiliary subunits such as DPP6 (dipeptidyl peptidase–like protein 6) and KChIP2 (Kv channel–interacting protein 2), in neurodegenerative diseases. Both observational and experimental designs were considered. Data extraction included disease type, model, Kv4 subunit, functional or genetic findings, and key outcomes. Risk of bias was assessed in all included studies. Results: Kv4 channels exhibit significant functional and expression changes in various neurodegenerative diseases. In AD and prionopathies, reduced Kv4.1- and Kv4.2-mediated currents contribute to neuronal hyperexcitability. In spinocerebellar ataxias, KCND3 mutations cause loss- or gain-of-function phenotypes in Kv4.3, disrupting cerebellar signaling. In models of ALS and PD, Kv4 dysfunction correlates with altered neuronal excitability and can be modulated pharmacologically. Subunit modulators such as DPP6 and KChIP2 influence channel function and could represent therapeutic targets. Conclusions: Kv4 channels are crucial for neuronal excitability in multiple neurodegenerative contexts. Dysregulation through genetic or pathological mechanisms contributes to functional deficits, highlighting Kv4 channels as promising targets for interventions aimed at restoring electrical homeostasis and mitigating early neuronal dysfunction. Full article

The existence of s-DAPK-1, an alternatively spliced variant of DAPK-1, adds complexity to our understanding of the proteins involved in the regulation of cell survival, apoptosis, and autophagy. DAPK-1 has been implicated in the regulation of these processes; however, it remains unclear whether s-DAPK-1 also plays a similar role or a separate function; thus, determining its involvement in these processes is challenging due to the limited understanding of its regulation, interacting partners, function, and three-dimensional (3D) structure. Hence, this study was aimed at (1) understanding the regulation of s-DAPK-1 by predicting its microRNA targets, (2) predicting the 3D structure of s-DAPK-1, (3) its physicochemical and thermodynamic properties, (4) its interacting partners, and (5) molecular functions using computational methods. To achieve this aim, various bioinformatics tools and in silico webservers, such as ProteinPrompt, ProtParam, ProtScale, ScooP, Hawkdock, Phyre2, I-TASSER, PSIPRED, SAVES, and PROCHECK, along with user-friendly databases, such as NCBI, TarBase, and Protein Data Bank (PDB), were employed. For miRNA prediction, we used TarBase, and identified the specific microRNAs targeting s-DAPK-1. Furthermore, the Phyre2 database demonstrated that s-DAPK-1 possesses 40% alpha helices and 4% beta strands, forming a stable 3D structure. Additionally, s-DAPK-1 demonstrated stability to withstand high temperatures, suggesting that it is a thermostable protein. Moreover, s-DAPK-1 was found to interact with a variety of proteins involved in tumor progression and gene regulation, including a prion protein and histone H2B type 2-E (H2B2E). This suggests that s-DAPK-1 may perform diverse molecular functions such as regulation of metabolic processes, nucleic acid binding, and mRNA splicing by interacting with different proteins. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

The assembly of amyloidogenic proteins and peptides into toxic oligomeric and fibrillar aggregates is closely connected to the onset and progression of more than 50 protein diseases, such as Alzheimer’s disease, Parkinson’s disease, prion disease, and type 2 diabetes, to name only a few. Considerable research efforts at identifying the therapeutic strategies against these maladies are currently focused on preventing and inhibiting pathogenic protein aggregation by various agents. Plant-based extracts and compounds have emerged as promising sources of potential inhibitors due to their dual role as nutraceuticals as part of healthy diets and as specific pharmaceuticals when administered at higher concentrations. In recent decades, several plant extracts and plant-extracted compounds have shown potential to modulate protein aggregation. An ever-growing body of research on plant-based amyloid inhibitors requires a detail analysis of existing data to identify potential knowledge gaps. This review summarizes the recent progress in amyloid inhibition using 17 flavonoids, 11 polyphenolic non-flavonoid compounds, 23 non-phenolic inhibitors, and 59 plant extracts, with the main emphasis on directly modulating the fibrillation of four amyloid proteins, namely amyloid-β peptide, microtubule-associated protein tau, α-synuclein, and human islet amyloid polypeptide. Full article

Chronic Wasting Disease (CWD) is a prion disease that affects Cervidae species, and is the only known prion disease transmitted among wildlife species. The key pathological feature is the conversion of the normal prion protein (PrP^C) misfolding into abnormal forms (PrP^Sc), triggering the onset of CWD infections. The misfolding can generate distinct PrP^Sc conformations (strains) giving rise to diverse disease phenotypes encompassing pathology, incubation period, and clinical signs. These phenotypes operationally define distinct prion strains, a pivotal element in monitoring CWD spread and zoonotic potential—a complex endeavor compounded by defining and tracking CWD strains. This review pursues a tripartite objective: 1. to address the intricate challenges inherent in ongoing CWD strain classification; 2. to provide an overview of the known CWD-infected isolates, the strains they represent and their passage history; and 3. to describe the spatial diversity of CWD strains in North America, enriching our understanding of CWD strain dynamics. By delving into these dimensions, this review sheds light on the intricate interplay among polymorphisms, biochemical properties, and clinical expressions of CWD. This endeavor aims to elevate the trajectory of CWD research, advancing our insight into prion disease. Full article

(1) Background: Parkinson’s disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) within neurons. Growing evidence indicates that α-syn may propagate throughout the nervous system in a manner similar to prion-like transmission. Extracellular vesicles (EVs) may contribute to this pathway. We and others have reported that ATP13A2/PARK9 deficiency results in decreased EVs while its overexpression leads to increased EV generation. For analyzing EV-mediated α-syn secretion in neighboring neurons, we planned to alter Atp13a2 levels in vivo. (2) Methods: Three months after inoculating mouse α-syn fibrils into the striatum of Atp13a2-null and wild-type mice, we stained brain sections with anti-phosphorylated α-syn antibodies and then quantified LBs/LNs. We also examined the effect of increased levels of ATP13A2 by injecting lentivirus carrying human ATP13A2. Finally, we used cultured astrocytes and microglia for α-syn uptake and release, which were mediated by EVs. (3) Results: While LBs/LNs were formed in the entire brains, no significant difference was observed in LB/LN formation between Atp13a2-deficient and wild-type mice. Interestingly, the overexpression of ATP13A2 led to decreased LB/LN formation in the entire brains. Microglia and astrocytes released EVs more than neurons. EVs released from microglia and astrocytes contained more α-syn PFFs than those from neurons. (4) Conclusions: These results suggest that enhanced EV secretion by increased ATP13A2 levels attenuate the spreading of α-syn in brains, suggesting a protective role of ATP13A2 in α-synucleinopathies Full article

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Currently, PD is incurable, and the diagnosis of PD mainly relies on clinical manifestations. The central pathological event in PD is the abnormal aggregation and deposition of misfolded α-synuclein (α-Syn) protein aggregates in the Lewy body (LB) in affected brain areas. Behaving as a prion-like seeding, the misfolded α-syn protein can induce and facilitate the aggregation of native unfolded α-Syn protein to aggravate α-Syn protein aggregation, leading to PD progression. Recently, in a blood-based α-Syn seeding amplification assay (SAA), Kluge et al. identified pathological α-Syn seeding activity in PD patients with Parkin (PRKN) gene variants. Additionally, pathological α-syn seeding activity was also identified in sporadic PD and PD patients with Leucine-rich repeat kinase 2 (LRRK2) or glucocerebrosidase (GBA) gene variants. Principally, the α-Syn SAA can be used to detect pathological α-Syn seeding activity, which will significantly enhance PD diagnosis, progression monitoring, prognosis prediction, and anti-PD therapy. The significance and future strategies of α-Syn SAA protocol are highlighted and proposed, whereas challenges and limitations of the assay are discussed. Full article

(1) Background: Creutzfeldt–Jakob disease (CJD) is a rare and fatal neurodegenerative disorder caused by the accumulation of an altered prion protein, which usually leads to death within one year after clinical onset. CJD patients usually present with rapid cognitive impairment associated with declines in cerebellar, motor, visual, behavioral, and swallowing functions. Moreover, CJD patients lose their ability to eat and take medications orally very early on in treatment; nevertheless, there are no specific nutritional guidelines for this disease shared worldwide. (2) Methods: This review aims to describe the nutritional outcomes of CJD patients in Western countries to compare them with those described in East Asian countries and then aims to explore the most recent trends in the nutritional management of CJD patients, including some dietary compounds that present neuroprotective effects. (3) Results: In Japan’s, Taiwan’s, and China’s healthcare systems, CJD patients receive intensive life-sustaining treatment that prolongs their survival (i.e., artificial feeding); conversely, in Western countries, intensive life-sustaining treatments like tube feeding are not commonly provided to CJD patients. (4) Conclusions: It is difficult to pinpoint the reasons for these discrepancies around CJD palliative care supply, but it is clear that specific nutritional guidelines may directly improve the nutritional management of CJD patients and thus allow their families and caregivers to ensure the best end-of-life care for these patients. Full article

Chronic wasting disease (CWD) is a prion disease afflicting wild and farmed elk. CWD prions (PrP^Sc) are infectious protein conformations that replicate by inducing a natively expressed prion protein (PrP^C) to refold into the prion conformation. Mass spectrometry was used to study the prions resulting from a previously described experimental inoculation of MM132, ML132, and LL132 elk with a common CWD inoculum. Chymotryptic digestion times and instrument parameters were optimized to yield a set of six peptides, TNMK, MLGSAMSRPL, LLGSAMSRPL, ENMYR, MMER, and VVEQMCITQYQR. These peptides were used to quantify the amount, the M132 and L132 polymorphic composition, and the extent of methionine oxidation of elk PrP^Sc. The amount (ng/g brain tissue) of PrP^Sc present in each sample was determined to be: MM132 (5.4 × 10² ± 7 × 10¹), ML132 (3.3 × 10² ± 6 × 10¹ and 3.6 × 10² ± 3 × 10¹) and LL132 (0.7 × 10² ± 1 × 10¹, 0.2 × 10² ± 0.2 × 10¹, and 0.2 × 10² ± 0.5 × 10¹). The proportion of L132 polymorphism in ML132 (heterozygous) PrP^Sc from CWD-infected elk was determined to be 43% ± 2% or 36% ± 3%. Methionine oxidation was detected and quantified for the M132 and L132 polymorphisms in the samples. In this way, mass spectrometry can be used to characterize prion strains at a molecular level. Full article

The screening of 166 extracts from tropical marine organisms (invertebrates, macroalgae) and 3 cyclolipopeptides from microorganisms against yeast prions highlighted the potential of Verongiida sponges to prevent the propagation of prions. We isolated the known compounds purealidin Q (1), aplysamine-2 (2), pseudoceratinine A (3), aerophobin-2 (4), aplysamine-1 (5), and pseudoceratinine B (6) for the first time from the Wallisian sponge Suberea laboutei. We then tested compounds 1–6 and sixteen other bromotyrosine and bromophenol derivatives previously isolated from Verongiida sponges against yeast prions, demonstrating the potential of 1–3, 5, 6, aplyzanzine C (7), purealidin A (10), psammaplysenes D (11) and F (12), anomoian F (14), and N,N-dimethyldibromotyramine (15). Following biological tests on mammalian cells, we report here the identification of the hitherto unknown ability of the six bromotyrosine derivatives 1, 2, 5, 7, 11, and 14 of marine origin to reduce the spread of the PrP^Sc prion and the ability of compounds 1 and 2 to reduce endoplasmic reticulum stress. These two biological activities of these bromotyrosine derivatives are, to our knowledge, described here for the first time, offering a new therapeutic perspective for patients suffering from prion diseases that are presently untreatable and consequently fatal. Full article

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer’s disease and over twenty neurodegenerative disorders. However, the molecular mechanisms of tau aggregation in vivo remain incompletely understood. There are two types of tau aggregates in the brain: soluble aggregates (oligomers and protofibrils) and insoluble filaments (fibrils). Compared to filamentous aggregates, soluble aggregates are more toxic and exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, in its native state, tau is a highly soluble, heat-stable protein that does not form fibrils by itself, not even when hyperphosphorylated. In vitro studies have found that negatively charged molecules such as heparin, RNA, or arachidonic acid are generally required to induce tau aggregation. Two recent breakthroughs have provided new insights into tau aggregation mechanisms. First, as an intrinsically disordered protein, tau is found to undergo liquid-liquid phase separation (LLPS) both in vitro and inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar tau conformations associated with different neurodegenerative disorders. Nonetheless, only the fibrillar core is structurally resolved, and the remainder of the protein appears as a “fuzzy coat”. From this review, it appears that further studies are required (1) to clarify the role of LLPS in tau aggregation; (2) to unveil the structural features of soluble tau aggregates; (3) to understand the involvement of fuzzy coat regions in oligomer and fibril formation. Full article

A group of functionalized fluorene derivatives that are structurally similar to the cellular prion protein ligand N,N′-(methylenedi-4,1-phenylene)bis [2-(1-pyrrolidinyl)acetamide] (GN8) have been synthesized. These compounds show remarkable native fluorescence due to the fluorene ring. The substituents introduced at positions 2 and 7 of the fluorene moiety are sufficiently flexible to accommodate the beta-conformational folding that develops in amyloidogenic proteins. Changes in the native fluorescence of these fluorene derivatives provide evidence of transformations in the amyloidogenic aggregation processes of insulin. The increase observed in the fluorescence intensity of the sensors in the presence of native insulin or amyloid aggregates suggest their potential use as fluorescence probes for detecting abnormal conformations; therefore, the compounds can be proposed for use as “turn-on” fluorescence sensors. Protein–sensor dissociation constants are in the 5–10 μM range and an intermolecular charge transfer process between the protein and the sensors can be successfully exploited for the sensitive detection of abnormal insulin conformations. The values obtained for the Stern–Volmer quenching constant for compound 4 as a consequence of the sensor–protein interaction are comparable to those obtained for the reference compound GN8. Fluorene derivatives showed good performance in scavenging reactive oxygen species (ROS), and they show antioxidant capacity according to the FRAP and DPPH assays. Full article

Scrapie is a neurodegenerative disease that impacts sheep and goats, characterized by gradual and progressive changes in neurological function. Recent research shows that the scrapie incubation period is significantly influenced by specific variations in amino acids within the prion protein gene (PRNP). The objective of this study was to estimate the national prevalence of caprine PRNP genetic variability at codons 146, 211, and 222 in goat populations across the United States. A total of 3052 blood, ear tissue, and brain tissue samples were collected from goats from 50 states. The participating states were categorized into four Veterinary Service (VS) district regions. The samples underwent DNA extraction, and the PRNP variants corresponding to codons 146, 211, and 222 were amplified and sequenced. The analysis of PRNP variants, when compared to the PRNP reference sequence, revealed seven alleles in twelve genotypes. The homozygous 146NN, 211RR, and 222QQ alleles, which have been linked to an increased risk of scrapie, were found to be the most prevalent among all the goats. The heterozygous 222QK, 211RQ, 146SD, 146ND, and 146NS alleles and the homozygous 222KK, 146SS, and 146DD alleles, known to be associated with reduced scrapie susceptibility and a prolonged incubation period after experimental challenge, were found in 1.098% (222QK), 2.33% (211RQ), 0.58% (146SD), 3.13% (146ND), 20.68% (146NS), 0.005% (222KK), 3.31% (146SS), and 0.67% (146DD) of goats, respectively. The 222QK allele was found most frequently in goats tested from the east (VS District 1, 1.59%) and southwest (VS District 4, 1.08%) regions, whereas the 211RQ allele was found most often in goats tested from the Midwest (VS District 2, 8.03%) and east (VS District 1, 6.53%) regions. The 146NS allele was found most frequently in goats tested from the northwest (VS District 3, 29.02%) and southwest (VS District 4, 20.69%) regions. Our results showed that the prevalence of less susceptible genotypes at PRNP codon 146 may be sufficient to use genetic susceptibility testing in some herds. This may reduce the number of goats removed as part of a herd clean-up plan and may promote the selective breeding goats for less susceptible alleles in high-risk herds at the national level. Full article