Stroke is the second leading cause of death and a major contributor to disability worldwide. The prevalence of stroke is highest in developing countries, with ischemic stroke being the most common type. Considerable progress has been made in our understanding of the pathophysiology of stroke and the underlying mechanisms leading to ischemic insult. Stroke therapy primarily focuses on restoring blood flow to the brain and treating stroke-induced neurological damage. Lack of success in recent clinical trials has led to significant refinement of animal models, focus-driven study design and use of new technologies in stroke research. Simultaneously, despite progress in stroke management, post-stroke care exerts a substantial impact on families, the healthcare system and the economy. Improvements in pre-clinical and clinical care are likely to underpin successful stroke treatment, recovery, rehabilitation and prevention. In this review, we focus on the pathophysiology of stroke, major advances in the identification of therapeutic targets and recent trends in stroke research.

Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1+2T>C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1+2T>C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs.

The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.

Changes in telomerase activity and telomere length contribute to aging-related decline. Investigating telomerase in aging models provides insights into related pathologies. Here, we present a protocol to detect telomerase activity in adult mouse hippocampal neural progenitor cells using the telomeric repeat amplification protocol assay. We describe steps for isolating and expanding aged mouse hippocampal neural progenitor cells (NPCs) and assessing telomerase using a non-radioactive technique. The protocol emphasizes the significance of understanding telomerase activity in NPCs for neurogenesis and age-related diseases.

While microRNAs (miRs) like miR-9 are crucial for neurogenesis and neuronal differentiation, their regulatory mechanisms are not well understood. miR-9 is highly expressed in the brain and plays a significant role in neurogenesis. Using the Collaborative Cross resource, we identified significant quantitative trait loci (QTL) through genetic analyses. We then characterized over 130 candidate genes within these QTL regions using RNA interference, qPCR, and neuronal differentiation assays, narrowing them down to 13 promising candidates. Among these, Panx2, Polr1c, and Mgea5 were found to colocalize in the neurogenic niches of the SVZ and DG regions, as shown by immunofluorescence. Further ChIP-seq and Co-IP analyses revealed their interaction and binding to the miR-9 locus, forming a DNA-protein regulatory complex we termed 'miRSome-9.' A 3C/ChIP-loop assay confirmed the chromatin organization of miRSome-9 at the miR-9 locus, shedding light on the upstream mechanisms regulating miR-9 expression during neurogenesis.

MiR-29a is essential for neuronal development and implicated in neurodegenerative disease, yet its upstream regulation remains unclear. Using genetically diverse Collaborative Cross (CC) mice, we performed expression profiling and QTL mapping, identifying a strong locus on chromosome 7. Among ten candidates, Psmd13 emerged as a key regulator. RNAi-mediated Psmd13 knockdown in mouse neural precursor cells (mNPCs) enhanced neuronal differentiation, with miR-29a upregulated in the undifferentiated state but reduced upon differentiation. Co-immunoprecipitation suggested an association between Psmd13 and Dicer, correlating with state-dependent changes in miR-29a levels. ChIP-seq revealed overlapping chromatin occupancy of Psmd13 and Dicer at several genomic loci, including miR-29a, consistent with—but not directly demonstrating—a role in chromatin accessibility and transcriptional control. Proteasome inhibition with MG132 lowered Psmd13 and Dicer, suppressed miR-29a, and impaired neuronal differentiation. Together, these findings suggest that differentiation dynamically regulates miR-29a expression through Psmd13–Dicer interactions, supporting a model in which Psmd13 acts as an upstream modulator of miRNA control and neurodevelopmental homeostasis.