Recent studies have elucidated various molecular mechanisms underlying neurodegeneration, particularly focusing on the roles of specific proteins and genetic mutations. For instance, Khazaei et al. demonstrated that germline histone H3.3 substitutions, notably H3.3G34R/V, lead to severe neurodevelopmental syndromes and progressive neurodegeneration in knock-in mice, characterized by microcephaly and neuronal depletion (ref: Khazaei doi.org/10.1016/j.cell.2023.02.023/). Similarly, Mukadam et al. highlighted the importance of the cytosolic antibody receptor TRIM21 in tau immunotherapy, showing that it plays a crucial role in protecting against tau pathology in mouse models (ref: Mukadam doi.org/10.1126/science.abn1366/). Neel et al. further contributed to this theme by identifying Gasdermin-E as a mediator of mitochondrial damage in axons, linking it to neurodegeneration, which underscores the importance of mitochondrial integrity in neuronal health (ref: Neel doi.org/10.1016/j.neuron.2023.02.019/). Praschberger et al. explored the cell-type-specific toxicity of α-synuclein and tau, revealing that neuronal identity influences their pathogenic effects, suggesting that intrinsic properties of neurons may dictate their vulnerability to these proteins (ref: Praschberger doi.org/10.1016/j.neuron.2023.02.033/). Lastly, Lee et al. reported that downregulation of Hsp90 and antimicrobial peptide Mtk can mitigate poly(GR)-induced neurotoxicity in C9ORF72-related ALS/FTD, indicating potential therapeutic targets for these conditions (ref: Lee doi.org/10.1016/j.neuron.2023.02.029/).

Neuroinflammation plays a pivotal role in the pathogenesis of various neurodegenerative diseases, as evidenced by several recent studies. Gao et al. identified β2-microglobulin as an endogenous NMDAR antagonist that impairs synaptic function, particularly in the context of Down syndrome, suggesting a link between immune factors and synaptic integrity (ref: Gao doi.org/10.1016/j.cell.2023.01.021/). Mi et al. further explored the metabolic role of astrocytic mitochondria, demonstrating that loss of fatty acid degradation leads to neuroinflammation and neurodegeneration, highlighting the critical support astrocytes provide to neurons (ref: Mi doi.org/10.1038/s42255-023-00756-4/). Zhou et al. focused on the neuronal pentraxin Nptx2, revealing its regulatory role in complement activity and microglial-mediated synapse loss, which could have implications for therapeutic strategies in diseases like Alzheimer's and frontotemporal dementia (ref: Zhou doi.org/10.1126/scitranslmed.adf0141/). These findings collectively underscore the intricate interplay between immune responses and neurodegenerative processes, suggesting that targeting neuroinflammatory pathways may offer new therapeutic avenues.

The interplay of genetic and environmental factors in neurodegenerative diseases has been a focal point of recent research. Ueda et al. conducted a cohort study on male elite football players, revealing a significantly higher risk of neurodegenerative diseases compared to matched controls, with a hazard ratio of 1.46, indicating that professional sports may contribute to long-term neurological risks (ref: Ueda doi.org/10.1016/S2468-2667(23)00027-0/). Elena-Real et al. investigated the structural basis of Huntington's disease, linking the aggregation propensity of the pathogenic huntingtin protein to its polyglutamine tract length, thus providing insights into the genetic underpinnings of this disorder (ref: Elena-Real doi.org/10.1038/s41594-023-00920-0/). Zheng et al. examined the longitudinal association between physical frailty and the development of Parkinson's disease, emphasizing the role of genetic predisposition in this relationship (ref: Zheng doi.org/10.1001/jamaneurol.2023.0183/). Coomans et al. utilized genetically identical twin-pair difference models to support the amyloid cascade hypothesis, demonstrating strong associations between amyloid-β levels and cognitive decline, thereby reinforcing the genetic contributions to neurodegenerative processes (ref: Coomans doi.org/10.1093/brain/). Ding et al. identified mutations in the ARHGEF15 gene as a causal factor for hereditary cerebral small vessel disease, further illustrating the genetic landscape of neurodegenerative conditions (ref: Ding doi.org/10.1007/s00401-023-02560-6/).

Innovative therapeutic approaches and the identification of biomarkers are crucial for advancing the treatment of neurodegenerative diseases. Próchnicki et al. discovered that mitochondrial damage activates the NLRP10 inflammasome, which could represent a novel target for therapeutic intervention aimed at mitigating neuroinflammation (ref: Próchnicki doi.org/10.1038/s41590-023-01451-y/). Ashton et al. highlighted the potential of serum biomarkers, finding significantly elevated levels of p-tau in cardiac arrest patients with poor neurological outcomes, suggesting that these biomarkers could aid in early diagnosis and prognosis of neurodegenerative diseases (ref: Ashton doi.org/10.1001/jamaneurol.2023.0050/). Anderson et al. employed single nucleus multiomics to identify ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific transcriptional changes, providing insights into the regulatory mechanisms underlying the disease (ref: Anderson doi.org/10.1016/j.xgen.2023.100263/). Marie et al. developed a label-free workflow for profiling N-glycans, which could serve as sensitive biomarkers for various diseases, including neurodegenerative disorders (ref: Marie doi.org/10.1038/s41467-023-37365-4/). Manolaras et al. demonstrated that CoQ10 treatment rescues mitochondrial dysfunction in COQ8A-ataxia Purkinje neurons, indicating a potential therapeutic strategy for this rare neurodegenerative disorder (ref: Manolaras doi.org/10.1093/brain/).

Advancements in experimental techniques and disease models are enhancing our understanding of neurodegenerative diseases. Grandjean et al. introduced a consensus protocol for functional connectivity analysis in rat brains, which facilitates comparisons across studies and enhances the reproducibility of findings in neuroimaging (ref: Grandjean doi.org/10.1038/s41593-023-01286-8/). Chapman et al. developed a noninflammatory demyelination model using two-photon imaging, allowing for real-time observation of oligodendrocyte dynamics during remyelination, which is critical for understanding myelin repair mechanisms (ref: Chapman doi.org/10.1038/s41593-023-01271-1/). Neel et al. also contributed to this theme by identifying the role of Gasdermin-E in mitochondrial damage and neurodegeneration, emphasizing the importance of mitochondrial health in neurodegenerative processes (ref: Neel doi.org/10.1016/j.neuron.2023.02.019/). Hackstein et al. explored the systemic T-cell dysfunction in chronic liver injury, which may have implications for understanding immune responses in neurodegenerative diseases (ref: Hackstein doi.org/10.1016/j.jhep.2023.02.026/). Hasanova et al. characterized human senataxin as an R-loop resolving enzyme, linking transcriptional regulation to neurodegenerative disorders, thus providing a novel angle for therapeutic exploration (ref: Hasanova doi.org/10.1093/nar/).

Cognitive decline is a significant aspect of neurodegenerative diseases, with various factors influencing its progression. Wooten et al. examined racial and ethnic differences in subjective cognitive decline, highlighting the prevalence of cognitive symptoms in older adults and their potential link to early-stage dementia (ref: Wooten doi.org/10.15585/mmwr.mm7210a1/). Zheng et al. investigated the longitudinal association between physical frailty and Parkinson's disease, revealing that frailty may serve as a predictor for cognitive decline in this population (ref: Zheng doi.org/10.1001/jamaneurol.2023.0183/). Malpetti et al. assessed microglial activation in frontotemporal dementia, finding that increased activation predicts faster cognitive decline, thus emphasizing the role of neuroinflammation in cognitive deterioration (ref: Malpetti doi.org/10.1093/brain/). Winfree et al. discovered that TREM2 gene expression is region-specific in relation to Alzheimer's disease neuropathology, suggesting that microglial responses may vary across brain regions and influence cognitive outcomes (ref: Winfree doi.org/10.1007/s00401-023-02564-2/). Bocancea et al. identified education as a robust determinant of cognitive resilience against tau pathology, indicating that demographic factors can significantly influence cognitive health in the context of neurodegeneration (ref: Bocancea doi.org/10.1093/brain/).

The study of protein aggregation and misfolding is crucial for understanding the pathophysiology of neurodegenerative diseases. Wątor et al. provided insights into the hypusination process of eIF5A, linking it to neurodegenerative disorders through structural analysis of the eIF5A-DHS complex, thereby revealing potential therapeutic targets (ref: Wątor doi.org/10.1038/s41467-023-37305-2/). Choong et al. investigated the interaction between phosphatidylinositol-3,4,5-trisphosphate and α-synuclein, demonstrating that this lipid initiates α-synuclein aggregation, which is a hallmark of Parkinson's disease (ref: Choong doi.org/10.1007/s00401-023-02555-3/). Kragelj et al. focused on intrinsically disordered proteins, developing a simulation framework to elucidate the conformational ensembles that explain NMR spectra, thus advancing the understanding of protein dynamics in neurodegenerative contexts (ref: Kragelj doi.org/10.1002/pro.4628/). Neel et al. also contributed to this theme by identifying Gasdermin-E's role in mitochondrial damage and neurodegeneration, linking protein misfolding to cellular dysfunction (ref: Neel doi.org/10.1016/j.neuron.2023.02.019/). These studies collectively highlight the multifaceted nature of protein aggregation and its implications for neurodegenerative diseases.

Clinical and epidemiological studies are essential for understanding the prevalence and risk factors associated with neurodegenerative diseases. Robinson et al. reported that pathological combinations in neurodegenerative diseases are heterogeneous, with only a minority of cases classified as neurodegenerative alone, emphasizing the complexity of these conditions (ref: Robinson doi.org/10.1093/brain/). Nichols et al. harmonized neuropathology measures across multiple community-based autopsy studies, revealing the prevalence and co-occurrence of neuropathologies in the aging population, which provides valuable insights into dementia's multifactorial nature (ref: Nichols doi.org/10.1016/S2666-7568(23)00019-3/). Ueda et al. assessed the risk of neurodegenerative diseases among elite football players, finding a significantly higher incidence compared to controls, which raises concerns about the long-term neurological impacts of contact sports (ref: Ueda doi.org/10.1016/S2468-2667(23)00027-0/). Zheng et al. explored the relationship between physical frailty and Parkinson's disease, highlighting the importance of longitudinal studies in understanding disease progression (ref: Zheng doi.org/10.1001/jamaneurol.2023.0183/). These findings underscore the need for continued research into the epidemiology of neurodegenerative diseases to inform prevention and intervention strategies.