FMRP Long-Range Transport and Degradation Are Mediated by Dynlrb1 in Sensory Neurons.

The fragile X messenger ribonucleoprotein 1 (FMRP) is a multifunctional RNA-binding protein implicated in human neurodevelopmental and neurodegenerative disorders. FMRP mediates the localization and activity-dependent translation of its associated mRNAs through the formation of phase-separated condensates that are trafficked by microtubule-based motors in axons. Axonal transport and localized mRNA translation are critical processes for long-term neuronal survival and are closely linked to the pathogenesis of neurological diseases. FMRP dynein-mediated axonal trafficking is still largely unexplored but likely to constitute a key process underlying FMRP spatiotemporal translational regulation. Here, we show that dynein light chain roadblock 1 (Dynlrb1), a subunit of the dynein complex, is a critical regulator of FMRP function. In sensory axons, FMRP associates with endolysosomal organelles, likely through annexin A11, and is retrogradely trafficked by the dynein complex in a Dynlrb1-dependent manner. Moreover, Dynlrb1 silencing induced FMRP granule accumulation and repressed the translation of microtubule-associated protein 1b, one of its primary mRNA targets. Our findings suggest that Dynlrb1 regulates FMRP function through the control of its transport and targeted degradation.

Anterograde Axonal Transport in Neuronal Homeostasis and Disease.

Neurons are highly polarized cells with an elongated axon that extends far away from the cell body. To maintain their homeostasis, neurons rely extensively on axonal transport of membranous organelles and other molecular complexes. Axonal transport allows for spatio-temporal activation and modulation of numerous molecular cascades, thus playing a central role in the establishment of neuronal polarity, axonal growth and stabilization, and synapses formation. Anterograde and retrograde axonal transport are supported by various molecular motors, such as kinesins and dynein, and a complex microtubule network. In this review article, we will primarily discuss the molecular mechanisms underlying anterograde axonal transport and its role in neuronal development and maturation, including the establishment of functional synaptic connections. We will then provide an overview of the molecular and cellular perturbations that affect axonal transport and are often associated with axonal degeneration. Lastly, we will relate our current understanding of the role of axonal trafficking concerning anterograde trafficking of mRNA and its involvement in the maintenance of the axonal compartment and disease.

Chemotherapy and cognition: comprehensive review on doxorubicin-induced chemobrain.

Chemobrain refers to a common sequela experienced by a substantial subset of cancer patients exposed to chemotherapeutic treatment, a phenomenon that dramatically deteriorates the survivors' quality of life and prevents them from restoring their pre-cancer life. This review is intended to address the current knowledge regarding the mechanisms underlying the pathophysiology of the chemobrain phenomenon, with special focus on the antineoplastic agent ''doxorubicin'', which has been shown to be implicated in strenuous central neurotoxicity despite being-almost entirely-peripherally confined. Moreover, the assessment of the post-chemotherapy cognitive impairment in both human and animal subjects, and the potential pharmacotherapy and behavioral intervention strategies are reviewed.

Astaxanthin Ameliorates Doxorubicin-Induced Cognitive Impairment (Chemobrain) in Experimental Rat Model: Impact on Oxidative, Inflammatory, and Apoptotic Machineries.

Chemobrain refers to a common sequelae experienced by 15-80% of cancer patients exposed to chemotherapeutics. The antineoplastic agent doxorubicin (DOX) has been implicated in a strenuous neurotoxicity manifested as decline in cognitive functions, most probably via cytokine-induced oxidative and nitrosative damage to brain tissues. Astaxanthin (AST), a naturally occurring carotenoid, is reputable for its outstanding antioxidant, anti-inflammatory, and antiapoptotic activities. Therefore, the aim of the current study was to investigate the potential neuroprotective and memory-enhancing effects of AST against DOX-induced behavioral and neurobiological abnormalities. Briefly, AST treatment (25 mg/kg) significantly protected against DOX-induced memory impairment. Furthermore, AST restored hippocampal histopathological architecture, halted DOX-induced oxidative and inflammatory insults, mitigated the increase in acetylcholinesterase activity, and consistently downregulated the overactive apoptotic machineries. In conclusion, these findings suggest that AST offers neuroprotection against DOX-induced cognitive impairment which could be explained at least partly by its antioxidant, anti-inflammatory, and antiapoptotic effects.