Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf ) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions. IntroductionAutosomal dominant mutations in RNA/DNA binding protein fused in sarcoma/translocated in liposarcoma (FUS/TLS) have been causally linked to familial ALS (FALS). The main pathological features in FALS with FUS mutations are FUS-positive protein aggregates in neuronal cytoplasm and dendrites (1, 2). While the majority of these aggregates are identified in the spinal motor neurons, FUS-positive aggregates have also been found in neurons in cerebral cortex and brainstem nuclei (3, 4), raising the possibility that FUS mutations may have a broader impact on the functions of other neuronal subtypes. Consistent with these observations, a subset of FALS-FUS patients also exhibits cognitive impairments during the developmental or degenerative processes.Although the exact mechanism of FUS mutations remains unclear, several previous studies have provided compelling evidence that FUS can regulate DNA damage response, transcription, and RNA processing. For instance, fibroblasts and lymphocytes from fus-null mice show increased sensitivity to ionizing irradiation and genomic instability, respectively (5, 6). Consistent with these results, our recent study shows that WT FUS proteins are rapidly recruited to DNA damage foci in neurons, where it interacts with histone deacetylase 1 (HDAC1), a critical component in

Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf ) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.

IntroductionOver 350 000 sacral neuromodulation (SNM) devices have been implanted since approval by the Food and Drug Administration (FDA) in 1998. SNM technology and clinical applications have evolved, with minimal safety updates after initial trials. We aim to provide an updated overview of real‐world SNM safety. These insights will guide informed consent, preoperative counseling, and patient expectation‐setting.Materials and MethodsThe FDA Manufacturer and User Facility Device Experience (MAUDE) database is a repository for medical device safety reports. We performed MAUDE categorical (1/1/98‐12/31/10) and keyword (1/1/11‐9/30/21) searches for “Interstim.” A random sample of 1000 reports was reviewed and categorized by theme. To corroborate our MAUDE database analysis, a legal librarian searched the Public Access to Court Electronic Records (PACER) database, as well as Bloomberg Law's dockets database for all lawsuits related to SNM devices.ResultsOur search of the MAUDE database returned 44 122 SNM‐related adverse events (AEs). The figure illustrates the prevalence of event categories in the random sample. The largest proportion of reports (25.6%) related to a patient's need for assistance with device use, followed by loss/change of efficacy (19.0%). Interestingly, a fall preceded issue onset in 32% of non‐shock pain, 30% of lead/device migration, and 27% of painful shock reports. Our legal search revealed only four lawsuits: one for patient complications after an SNM device was used off‐label, one case of transverse myelitis after implant, one for device migration or poor placement, and the fourth claimed the device malfunctioned requiring removal and causing permanent injury.ConclusionsThis review confirms the real‐world safety of SNM devices and very low complication rates as seen in the original clinical trials. Our findings indicate that 43.2% (95% confidence interval 40.1%–46.3%) of SNM “complications” are not AEs, per se, but rather reflect a need for improved technical support or more comprehensive informed consent to convey known device limitations to the patient, such as battery life. Similarly, the number of lawsuits is shockingly low for a device that has been in the market for 24 years, reinforcing the safety of the device. Legal cases involving SNM devices seem to relate to inappropriate patient selection—including at least one case in which SNM was used for a non‐FDA approved indication—lack of appropriate follow‐up, and/or provider inability to assist the patient with utilizing the device after implantation.