 |
By Michalina Hanzel, PhD
Fused in sarcoma (FUS) is a ribonucleoprotein that continuously shuttles between the nucleus and the cytoplasm to regulate pre-mRNA splicing, mRNA stability and mRNA transport. Mutations in FUS are found in 4% familial and 1% sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects the spinal motor neurons and leads to loss of motor control, muscle weakness and early death. Mutations both in the coding, as well as in the untranslated regions of the FUS gene lead to development of the disease. Interestingly, some of these mutations lead to the elevation of the wild type FUS protein levels, which also induces neurodegeneration. In a mouse disease model, overexpression of the human FUS protein causes aggressive ALS phenotype with neuron degeneration and astrogliosis. The mechanisms of FUS action in the disease progression have not been identified, but a recent paper1 sheds light on this important question.
Degeneration of motor neurons is caused by both the cell intrinsic vulnerabilities2, as well as the toxic microenvironment3. The latter is usually mediated by astrocytes and microglia, which coordinate the inflammatory response during disease progression. This mechanism was recently discussed in the blog Mechanisms of Neurodegeneration: Neuroinflammation and microglial activation. In ALS patients, there is an increased production of harmful inflammatory mediators, as well as upregulation of the master regulator of inflammation, NF-κB. Importantly, FUS can interact with NF-κB, therefore its dysregulation may affect the inflammatory responses in the patient cells, leading to a toxic environment and motor neuron loss.
Rat cortical stem cells differentiated into astrocytes were stained with a GFAP monoclonal antibody (MAB2594) for 3 hours at 10 μg/mL followed by anti-mouse IgG secondary antibody (NL007) conjugated with NorthernLights™ 557. DAPI was used to label the nuclei.
Learn more about neuroinflammation »
To investigate the relationship between increased production of FUS and astrocyte function, the authors used mouse and human neural progenitor cells derived from the spinal cord and differentiated them into astrocytes that conditionally overexpressed the wild type FUS protein. The results clearly indicated that increase in FUS levels in mouse and human astrocytes leads to a dysregulation of many proteins associated with the inflammatory response, and a more reactive phenotype of the astrocytes compared to control cells. The authors examined the modified astrocytes further by mimicking an inflammatory environment with a pro-inflammatory IL-1 beta stimulus. In this abnormal environment, the astrocytes that overexpressed the wild type FUS showed enhanced expression of inflammatory genes, promoted neuronal cell death, and enhanced pro-inflammatory activation of microglia . Overall, the results suggest that increase in wild type FUS levels changes the intrinsic reactivity of astrocytes, leading to their enhanced inflammatory phenotype (increased IL-6, TNF-alpha and PTGS2/COX-2 expression), which ultimately results in neurotoxicity. Hence, patient motor neurons in the vicinity of reactive astrocytes have increased chance of degeneration due to non-cell autonomous mechanisms.
This study is among dozens of others that have in recent years shifted our understanding of neurodegeneration as a cell-autonomous process, to a broader view of the neuron within its microenvironment. However, like most neurodegenerative disorders, ALS is complex and appears to have many cell intrinsic2, as well as cell non-autonomous vulnerabilities that are still being investigated.
Michalina Hanzel, PhD
Postdoctoral Associate at The Rockefeller University
Dr. Hanzel is currently studying synaptic function in the cerebellum to understand neurodevelopmental disorders and has a background in developmental neurobiology, molecular and cell biology.
References
