In neurons, the endoplasmic reticulum (ER) forms a highly dynamic network that enters axons and presynaptic terminals and plays a central role in Ca2+ homeostasis and synapse maintenance; however, the underlying mechanisms involved in regulation of its dynamic remodeling as well as its function in axon development and presynaptic differentiation remain elusive. Here, we used high-resolution microscopy and live-cell imaging to investigate rapid movements of the ER and ribosomes in axons of cultured motoneurons after stimulation with brain-derived neurotrophic factor. Our results indicate that the ER extends into axonal growth cone filopodia, where its integrity and dynamic remodeling are regulated mainly by actin and the actin-based motor protein myosin VI (encoded by Myo6). Additionally, we found that in axonal growth cones, ribosomes assemble into 80S subunits within seconds and associate with the ER in response to extracellular stimuli, which describes a novel function of axonal ER in dynamic regulation of local translation. This article has an associated First Person interview with Chunchu Deng, joint first author of the paper.

Previous studies have revealed that muscle atrophy emerges as a significant challenge faced by astronauts during prolonged missions in space. A loss in muscle mass results in a weakening of skeletal muscle strength and function, which will not only contribute to a decline in overall physical performance but also elevate the risk of various age-related diseases. Skeletal muscle atrophy in the microgravity environment is thought to be associated with changes in energy metabolism, protein metabolism, calcium ion homeostasis, myostatin levels, and apoptosis. Modulating some pathways could be a promising approach to mitigating muscle atrophy in the microgravity environment. This review serves as a comprehensive summary of research on the impact of microgravity on skeletal muscle, with the aim of providing insights into its pathogenesis and the development of effective treatments.

Plastin 3 (PLS3) is an F-actin-bundling protein that has gained attention as a modifier of spinal muscular atrophy (SMA) pathology. SMA is a lethal pediatric neuromuscular disease caused by loss of or mutations in the Survival Motor Neuron 1 (SMN1) gene. Pathophysiological hallmarks are cellular maturation defects of motoneurons prior to degeneration. Despite the observed beneficial modifying effect of PLS3, the mechanism of how it supports F-actin-mediated cellular processes in motoneurons is not yet well understood. Our data reveal disturbed F-actin-dependent translocation of the Tropomyosin receptor kinase B (TrkB) to the cell surface of Smn-deficient motor axon terminals, resulting in reduced TrkB activation by its ligand brain-derived neurotrophic factor (BDNF). Improved actin dynamics by overexpression of hPLS3 restores membrane recruitment and activation of TrkB and enhances spontaneous calcium transients by increasing Cav2.1/2 “cluster-like” formations in SMA axon terminals. Thus, our study provides a novel role for PLS3 in supporting correct alignment of transmembrane proteins, a key mechanism for (moto)-neuronal development.

Peripheral nerve injury (PNI) remains a significant clinical challenge, often leading to long-term functional impairment. Despite advances in therapies, current repair strategies offer unsatisfactory clinical outcomes. Exosomes derived from induced pluripotent stem cells (iPSC-Exos) have emerged as a promising therapeutic approach in regenerative medicine. This study assesses the efficacy and safety of iPSC-Exos in a rat model of sciatic nerve crush injury. Briefly, iPSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors using Sendai virus vectors and validated for pluripotency. iPSC-Exos were characterized and injected at the injury site. Functional recovery was assessed through gait analysis, grip strength, and pain response. Histological and molecular analyses were used to examine axonal regeneration, myelination, Schwann cell (SC) activation, angiogenesis, and changes in gene expression. iPSC-Exos were efficiently internalized by SC, promoting their proliferation. No adverse effects were observed between groups on body weight, organ histology, or hematological parameters. iPSC-Exos injection significantly enhanced nerve regeneration, muscle preservation, and vascularization, with RNA sequencing revealing activation of PI3K-AKT and focal adhesion pathways. These findings support iPSC-Exos as a safe and effective non-cell-based therapy for PNIs, highlighting their potential for clinical applications in regenerative medicine.

The presence of hyperphosphorylated Tau proteins, which mislocalize and form neurofibrillary tangles, and the accumulation of amyloid-β plaques are hallmark features of Alzheimer’s disease (AD). These toxic protein aggregates contribute to synaptic impairment and neuronal dysfunction, underscoring the need for strategies aimed at effectively clearing or reducing these aggregates in the treatment of AD. In recent years, proteolysis targeting chimera (PROTAC) technology has emerged as a promising approach for selectively degrading dysfunctional proteins rather than merely inhibiting their function. This approach holds great potential for developing more effective interventions that could slow AD progression and improve patient outcomes. In this review, we first examine the pathological mechanisms underlying AD, focusing on abnormal protein degradation and accumulation. We then explore the evolution of PROTAC technology, its mechanisms of action, and the current status of drug development. Finally, we discuss the latest findings regarding the application of PROTACs in AD therapy, highlighting the potential benefits and limitations of this technology. Although promising, further clinical research is necessary to fully assess the safety and efficacy of PROTAC-based therapies for AD treatment.

Small extracellular vesicles (sEVs), including exosomes as a subtype, with a diameter typically less than 200 nm and originating from the endosomal system, are capable of transporting a diverse array of bioactive molecules, including proteins, nucleic acids, and lipids, thereby facilitating intercellular communication and modulating cellular functions. Vascular dementia (VaD) represents a form of cognitive impairment attributed to cerebrovascular disease, characterized by a complex and multifaceted pathophysiological mechanism. Currently, the therapeutic approach to VaD predominantly emphasizes symptom management, as no specific pharmacological treatment exists to cure the condition. Recent investigations have illuminated the significant role of sEVs in the pathogenesis of vascular dementia. This review seeks to provide a comprehensive analysis of the characteristics and functions of sEVs, with a particular focus on their involvement in vascular dementia and its underlying mechanisms. The objective is to advance the understanding of the interplays between sEVs and vascular dementia, thereby offering novel insights for future research and therapeutic strategies.