Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments

Salcedo-Arellano, María Jimena; Cabal-Herrera, Ana María; Punatar, Ruchi; Clark, Courtney; Hagerman, Randi J

doi:10.1007/s13311-020-00968-6

Cited by 22 publications

(17 citation statements)

References 253 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Fragile X syndrome (FXS) is probably the best example of a disease linked to defects in intra-dendritic mRNA translation as reviewed by Swanger and Bassell [ 59 ]. FXS is the most frequent monogenic autism spectrum disorder (ASD), accounting for 2% of all cases [ 78 ], and is caused by a mutation in the fragile X mental retardation 1 ( FMR1 ) gene which causes loss of FMRP protein. FMRP is a RBP that negatively regulates protein synthesis as well as mRNA stability and transport.…”

Section: Neuronal Rna Localization Local Translation and Nervous mentioning

confidence: 99%

See 1 more Smart Citation

RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons

Blanco‐Urrejola

Gaminde-Blasco

Gamarra

et al. 2021

Cells

View full text Add to dashboard Cite

Cell polarity is crucial for almost every cell in our body to establish distinct structural and functional domains. Polarized cells have an asymmetrical morphology and therefore their proteins need to be asymmetrically distributed to support their function. Subcellular protein distribution is typically achieved by localization peptides within the protein sequence. However, protein delivery to distinct cellular compartments can rely, not only on the transport of the protein itself but also on the transport of the mRNA that is then translated at target sites. This phenomenon is known as local protein synthesis. Local protein synthesis relies on the transport of mRNAs to subcellular domains and their translation to proteins at target sites by the also localized translation machinery. Neurons and glia specially depend upon the accurate subcellular distribution of their proteome to fulfil their polarized functions. In this sense, local protein synthesis has revealed itself as a crucial mechanism that regulates proper protein homeostasis in subcellular compartments. Thus, deregulation of mRNA transport and/or of localized translation can lead to neurological and neurodegenerative diseases. Local translation has been more extensively studied in neurons than in glia. In this review article, we will summarize the state-of-the art research on local protein synthesis in neuronal function and dysfunction, and we will discuss the possibility that local translation in glia and deregulation thereof contributes to neurological and neurodegenerative diseases.

show abstract

Section: Neuronal Rna Localization Local Translation and Nervous mentioning

confidence: 99%

“…As previously mentioned, FXS is the most common inheritable form of ASD caused by loss of FMRP [ 78 ]. The RBP FMRP selectively binds 4% of brain mRNAs, including Mbp , to regulate their transport, translation, and stability [ 119 ].…”

Section: Rna Localization and Localized Translation In Gliamentioning

confidence: 99%

RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons

Blanco‐Urrejola

Gaminde-Blasco

Gamarra

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…Autism serves as an umbrella term encompassing many disorders and diseases, some of which have precise etiology (e.g., Down Syndrome [57], Fragile X Syndrome [58], etc.). In this work we posit that this broad spectrum affords subtyping and that given a random draw of genes linked to disorders with high penetrance in Autism, we could find selfemerging clusters at their intersection, using (probabilistic) distances from those overlapping genes specifically linked to Autism and their expression in brain-body tissues.…”

Section: Discussionmentioning

confidence: 99%

“…It will be interesting to track the evolution of these shared genes on induced pluripotent stem cell models, as cells develop into neuronal classes. Research along those lines is warranted [62]. Prostaglandin-endoperoxide synthase 2 PTGS2 or cyclooxygenase 2 COX2, is in 1q31.1.…”

Section: The Genes Common To Autism and Each Subtypementioning

confidence: 99%

Precision Autism: Genomic Stratification of Disorders Making Up the Broad Spectrum May Demystify its “Epidemic Rates”

Torres

2021

Preprint

View full text Add to dashboard Cite

In the last decade, Autism has broadened and often shifted its diagnostics criteria, allowing several neuropsychiatric and neurological disorders of known etiology. This has resulted in a highly heterogeneous spectrum with apparent exponential rates in prevalence. We ask if it is possible to leverage existing genetic information about those disorders making up Autism today and use it to stratify this spectrum. To that end, we combine genes linked to Autism in the SFARI database and genomic information from the DisGeNet portal on 25 diseases, inclusive of non-neurological ones. We use the GTEx data on genes' expression on 54 human tissues and ask if there are overlapping genes across those associated to these diseases and those from Autism-SFARI. We find a compact set of genes across all brain-disorders which express highly in tissues fundamental for somatic-sensory-motor function, self-regulation, memory, and cognition. Then, we offer a new stratification that provides a distance-based orderly clustering into possible Autism subtypes, amenable to design personalized targeted therapies within the framework of Precision Medicine. We conclude that viewing Autism through this physiological (Precision) lens, rather than from a psychological behavioral construct, may make it a more manageable condition and dispel the Autism epidemic myth.

show abstract

“…Autism Spectrum Disorders (ASD) and Fragile X Syndrome (FXS) Autism spectrum disorders is a term referred to heterogeneous behavioral disorders with a combination of difficulties in different areas including intellectual, communication or social interaction. The most common monogenic cause of ASD is FXS, a neurodevelopmental disorder which causes intellectual disability attributed to FMRP protein deficiency as a result of a mutation in the FMR1 gene (Salcedo-Arellano et al, 2020). One of the main cell-pathological features of FXS is the high levels of dendritic spines with an abnormal morphology linked to delayed maturation (Banerjee et al, 2018).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Local Translation in Nervous System Pathologies

Gamarra

Cruz

Blanco‐Urrejola

et al. 2021

Front. Integr. Neurosci.

View full text Add to dashboard Cite

Dendrites and axons can extend dozens to hundreds of centimeters away from the cell body so that a single neuron can sense and respond to thousands of stimuli. Thus, for an accurate function of dendrites and axons the neuronal proteome needs to be asymmetrically distributed within neurons. Protein asymmetry can be achieved by the transport of the protein itself or the transport of the mRNA that is then translated at target sites in neuronal processes. The latter transport mechanism implies local translation of localized mRNAs. The role of local translation in nervous system (NS) development and maintenance is well established, but recently there is growing evidence that this mechanism and its deregulation are also relevant in NS pathologies, including neurodegenerative diseases. For instance, upon pathological signals disease-related proteins can be locally synthesized in dendrites and axons. Locally synthesized proteins can exert their effects at or close to the site of translation, or they can be delivered to distal compartments like the nucleus and induce transcriptional responses that lead to neurodegeneration, nerve regeneration and other cell-wide responses. Relevant key players in the process of local protein synthesis are RNA binding proteins (RBPs), responsible for mRNA transport to neurites. Several neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis or spinal motor atrophy, are characterized by mutations in genes encoding for RBPs and consequently mRNA localization and local translation are impaired. In other diseases changes in the local mRNA repertoire and altered local protein synthesis have been reported. In this review, we will discuss how deregulation of localized translation at different levels can contribute to the development and progression of nervous system pathologies.

show abstract

Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments

Cited by 22 publications

References 253 publications

RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons

RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons

Precision Autism: Genomic Stratification of Disorders Making Up the Broad Spectrum May Demystify its “Epidemic Rates”

Local Translation in Nervous System Pathologies

Contact Info

Product

Resources

About