Downregulation of UBE4B promotes CNS axon regrowth and functional recovery after stroke.

The limited intrinsic regrowth capacity of corticospinal axons impedes functional recovery after cortical stroke. Although the mammalian target of rapamycin (mTOR) and p53 pathways have been identified as the key intrinsic pathways regulating CNS axon regrowth, little is known about the key upstream regulatory mechanism by which these two major pathways control CNS axon regrowth. By screening genes that regulate ubiquitin-mediated degradation of the p53 proteins in mice, we found that ubiquitination factor E4B (UBE4B) represses axonal regrowth in retinal ganglion cells and corticospinal neurons. We found that axonal regrowth induced by UBE4B depletion depended on the cooperative activation of p53 and mTOR. Importantly, overexpression of UbV.E4B, a competitive inhibitor of UBE4B, in corticospinal neurons promoted corticospinal axon sprouting and facilitated the recovery of corticospinal axon-dependent function in a cortical stroke model. Thus, our findings provide a translatable strategy for restoring corticospinal tract-dependent functions after cortical stroke.

Mitophagy in Cerebral Ischemia and Ischemia/Reperfusion Injury.

Ischemic stroke is a severe cerebrovascular disease with high mortality and morbidity. In recent years, reperfusion treatments based on thrombolytic and thrombectomy are major managements for ischemic stroke patients, and the recanalization time window has been extended to over 24 h. However, with the extension of the time window, the risk of ischemia/reperfusion (I/R) injury following reperfusion therapy becomes a big challenge for patient outcomes. I/R injury leads to neuronal death due to the imbalance in metabolic supply and demand, which is usually related to mitochondrial dysfunction. Mitophagy is a type of selective autophagy referring to the process of specific autophagic elimination of damaged or dysfunctional mitochondria to prevent the generation of excessive reactive oxygen species (ROS) and the subsequent cell death. Recent advances have implicated the protective role of mitophagy in cerebral ischemia is mainly associated with its neuroprotective effects in I/R injury. This review discusses the involvement of mitochondria dynamics and mitophagy in the pathophysiology of ischemic stroke and I/R injury in particular, focusing on the therapeutic potential of mitophagy regulation and the possibility of using mitophagy-related interventions as an adjunctive approach for neuroprotective time window extension after ischemic stroke.

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update.

Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.