Background:
Local protein synthesis and mRNA metabolism mediated by mRNP granules in the dendrites and the postsynaptic compartment is essential for synaptic remodeling and plasticity in neuronal cells. Dysregulation of these processes caused by TDP-43 proteinopathy leads to neurodegenerative diseases, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Methods:
Using biochemical analysis and imaging techniques, including super-resolution microscopy, we provide evidence, for the first time, for the postsynaptic localization of TDP-43 in mammalian synapses and we show that TDP-43 is a component of neuronal mRNP granules.
Results:
With activity stimulation and various molecular approaches, we further demonstrate activity-dependent mRNP granule dynamics involving disassembly of mRNP granules, release of mRNAs, activation of local protein translation, and the impairment of granule disassembly in cellular, animal and human models of TDP-43 proteinopathy.
Conclusion:
Our study elucidates the interplay between TDP-43 and neuronal mRNP granules in normal physiology and TDP-43 proteinopathy in the regulation of local protein translation and mRNA metabolism in the postsynaptic compartment.
BackgroundThe incidence of brain metastasis from colorectal cancer (CRC) increases along with the greater survival rate for CRC because of the advances in therapeutic modalities. Local treatment strategies for brain metastasis include surgical resection and radiotherapy. Nevertheless, given the incongruent literature, the optimal therapeutic approach remains to be investigated. This study aims to systematically compare the real-world survival outcome of surgical resection and radiotherapy in patients with brain metastasis from CRC.MethodsFollowing Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines (PROSPERO, ID: CRD42021240200), the Cochrane Library, Embase, and Medline were searched from the inception of the database to August 2021. Meta-analyses were conducted with results pooled using hazard ratios with corresponding 95% CIs to evaluate the overall survival (OS) following local treatment for brain metastasis from CRC. Summary effects were evaluated using a series of random-effect models.ResultsIn this review, 17 retrospective studies comprising 1,438 participants were included. In comparison with radiotherapy, the OS of patients who received brain metastasectomy was generally longer (HR, 0.53; 95% CI, 0.47–0.60). Extracerebral metastases (HR, 1.58; 95% CI, 1.34–1.86) and multiple brain metastases (HR, 1.38; 95% CI, 1.10–1.72) were associated with worse survival outcomes.ConclusionsFor patients with brain metastasis from CRC, the current real-world evidence demonstrated the survival benefit of aggressive neurosurgical management in suitable patients. Additionally, patients with extracerebral metastases and multiple brain metastases had worse survival outcomes.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=240200.
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