Synaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses

Deshpande, Dhruva; Higelin, Julia; Schoen, Michael; Vomhof, Thomas; Boeckers, Tobias M.; Demestre, Maria; Michaelis, Jens

doi:10.3389/fncel.2019.00256

Cited by 34 publications

(33 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…C to U mutations indicated with arrows and dashed circles, and 2-AP substitutions are denoted by solid circles. rodent synapses, and in human motoneurons derived from a healthy control induced pluripotent stem cells (Deshpande et al, 2019). Mouse studies suggest that synapses are significantly more susceptible to defects than axons and cell bodies when FUS is overexpressed or mutated (Sephton et al, 2016), indicating that FUS is important for synaptic plasticity and maintenance.…”

Section: Introductionmentioning

confidence: 99%

FUS Recognizes G Quadruplex Structures Within Neuronal mRNAs

Imperatore

McAninch

Valdez‐Sinon

et al. 2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

Fused in sarcoma (FUS), identified as the heterogeneous nuclear ribonuclear protein P2, is expressed in neuronal and non-neuronal tissue, and among other functions, has been implicated in messenger RNA (mRNA) transport and possibly local translation regulation. Although FUS is mainly localized to the nucleus, in the neurons FUS has also been shown to localize to the post-synaptic density, as well as to the pre-synapse. Additionally, the FUS deletion in cultured hippocampal cells results in abnormal spine and dendrite morphology. Thus, FUS may play a role in synaptic function regulation, mRNA localization, and local translation. Many dendritic mRNAs have been shown to form G quadruplex structures in their 3 ′ -untranslated region (3 ′ -UTR). Since FUS contains three arginine-glycine-glycine (RGG) boxes, an RNA binding domain shown to bind with high affinity and specificity to RNA G quadruplex structures, in this study we hypothesized that FUS recognizes these structural elements in its neuronal mRNA targets. Two neuronal mRNAs found in the pre-and post-synapse are the post-synaptic density protein 95 (PSD-95) and Shank1 mRNAs, which encode for proteins involved in synaptic plasticity, maintenance, and function. These mRNAs have been shown to form 3 ′ -UTR G quadruplex structures and were also enriched in FUS hydrogels. In this study, we used native gel electrophoresis and steady-state fluorescence spectroscopy to demonstrate specific nanomolar binding of the FUS C-terminal RGG box and of full-length FUS to the RNA G quadruplex structures formed in the 3 ′ -UTR of PSD-95 and Shank1a mRNAs. These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3 ′ -UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.

show abstract

Section: Introductionmentioning

confidence: 99%

FUS Recognizes G Quadruplex Structures Within Neuronal mRNAs

Imperatore

McAninch

Valdez‐Sinon

et al. 2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…However, a growing body of evidence has shown that FUS has an essential cytoplasmic role in neurons involved in transport and local protein translation, especially at the synapse. FUS has been shown to be located at both the pre- and post-synapse 8 , 9 as well as interacting with GluA1, the AMPA receptor subunit, which is a post-synaptic protein 10 . Evidence points towards FUS being essential for dendritic reorganisation by regulating synaptic mRNAs 11 , 12 with FUS depletion leading to a decrease in GluA1 expression resulting in supressed synaptic transmission and changes in synaptic maturation 10 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations

Salam

Tacconelli

Smith

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the ‘gain-of-function’ hypothesis for disease pathogenesis in FUS-related ALS.

show abstract

“…Of particular interest is a recent study in motor neurons derived from ALS patients in which an increased synaptic accumulation of mutated FUS is described, suggesting a role of synaptic FUS in both dendritic and axonal cellular compartments. In particular, a toxic gain‐of‐function due to the synaptic aggregation of mutant FUS was proposed (Deshpande et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis

Klingl

Pakravan

Bosch

2020

British J Pharmacology

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. ALS patients suffer from a progressive loss of motor neurons, leading to respiratory failure within 3 to 5 years after diagnosis. Available therapies only slow down the disease progression moderately or extend the lifespan by a few months. Epigenetic hallmarks have been linked to the disease, creating an avenue for potential therapeutic approaches. Interference with one class of epigenetic enzymes, histone deacetylases, has been shown to affect neurodegeneration in many preclinical models. Consequently, it is crucial to improve our understanding about histone deacetylases and their inhibitors in (pre)clinical models of ALS. We conclude that selective inhibitors with high tolerability and safety and sufficient blood–brain barrier permeability will be needed to interfere with both epigenetic and non‐epigenetic targets of these enzymes. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

show abstract

Synaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses

Cited by 34 publications

References 78 publications

FUS Recognizes G Quadruplex Structures Within Neuronal mRNAs

FUS Recognizes G Quadruplex Structures Within Neuronal mRNAs

Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations

Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis

Contact Info

Product

Resources

About