scholarly journals Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Dunhui Li ◽  
Craig Stewart McIntosh ◽  
Frank Louis Mastaglia ◽  
Steve Donald Wilton ◽  
May Thandar Aung-Htut
Keyword(s):  
Alternative Splicing ◽  
Neurodegenerative Diseases ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Single Gene ◽  
Synaptic Function ◽  
Coding Regions ◽  
Splicing Defects ◽  
The Impact ◽  
Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

scholarly journals The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets

Diabetes ◽  
2021 ◽  
pp. db200847
Author(s):  
Wenting Wu ◽  
Farooq Syed ◽  
Edward Simpson ◽  
Chih-Chun Lee ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Inflammatory Cytokines ◽  
Human Islets ◽  
The Impact ◽  
Splicing Patterns ◽  
Pro Inflammatory Cytokines

scholarly journals Decreased function of survival motor neuron protein impairs endocytic pathways

2016 ◽  
Vol 113 (30) ◽  
pp. E4377-E4386 ◽  
Author(s):  
Maria Dimitriadi ◽  
Aaron Derdowski ◽  
Geetika Kalloo ◽  
Melissa S. Maginnis ◽  
Patrick O’Hern ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Muscular Atrophy ◽  
Ultrastructural Level ◽  
Synaptic Function ◽  
Survival Motor Neuron ◽  
Endosomal Trafficking ◽  
Survival Motor Neuron Protein ◽  
Ribonucleoprotein Complexes ◽  
The Impact ◽  
Endocytic Pathways

Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.

scholarly journals Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

2020 ◽  
Author(s):  
Sunny Kumar ◽  
Daniel Phaneuf ◽  
Pierre Cordeau ◽  
Hejer Boutej ◽  
Jasna Kriz ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Oral Administration ◽  
Neurodegenerative Diseases ◽  
Mouse Models ◽  
Synaptic Function ◽  
Neurofilament Proteins ◽  
Type Iv ◽  
One Year ◽  
The Impact ◽  
The Brain

Abstract Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

The Impact of Natural Compounds on the Treatment of Neurodegenerative Diseases

2019 ◽  
Vol 23 (3) ◽  
pp. 335-360 ◽  
Author(s):  
Lorane I. da S. Hage-Melim ◽  
Jaderson V. Ferreira ◽  
Nayana K.S. de Oliveira ◽  
Lenir C. Correia ◽  
Marcos R.S. Almeida ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Muscular Atrophy ◽  
Neuronal Loss ◽  
The Elderly ◽  
Natural Compounds ◽  
Drug Candidates ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
The Impact

Neurodegenerative diseases (NDDs) are characterized by a progressive deterioration of the motor and/or cognitive function, that are often accompanied by psychiatric disorders, caused by a selective loss of neurons in the central nervous system. Among the NDDs we can mention Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia 3 (SCA3), spinal and bulbar muscular atrophy (SBMA) and Creutzfeldt-Jakob disease (CJD). AD and HD are characterized mainly by massive neuronal loss. PD, ALS, SCA3 and SBMA are agerelated diseases which have characteristic motor symptoms. CJD is an NDD caused by prion proteins. With increasing life expectancy, elderly populations tend to have more health problems, such as chronic diseases related to age and disability. Therefore, the development of therapeutic strategies to treat or prevent multiple pathophysiological conditions in the elderly can improve the expectation and quality of life. The attention of researchers has been focused on bioactive natural compounds that represent important resources in the discovery and development of drug candidates against NDDs. In this review, we discuss the pathogenesis, symptoms, potential targets, treatment and natural compounds effective in the treatment of AD, PD, HD, ALS, SCA3, SBMA and CJD.

scholarly journals Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD 

2020 ◽  
Author(s):  
Sunny Kumar ◽  
Daniel Phaneuf ◽  
Pierre Cordeau ◽  
Hejer Boutej ◽  
Jasna Kriz ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Oral Administration ◽  
Neurodegenerative Diseases ◽  
Mouse Models ◽  
Synaptic Function ◽  
Mice Model ◽  
Neurofilament Proteins ◽  
Type Iv ◽  
The Impact ◽  
The Brain

Abstract Background:TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown. Methods:Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used Ribotag with microarray and proteomic analysis to determine the neuronal translational profile in the mice model of ALS/FTD.Results:Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induced autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions:Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

81-OR: The Impact of Proinflammatory Cytokines on Human Pancreatic Islet Alternative Splicing Patterns

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 81-OR
Author(s):  
WENTING WU ◽  
FAROOQ SYED ◽  
EDWARD SIMPSON ◽  
CHIH-CHUN LEE ◽  
DECIO L. EIZIRIK ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Pancreatic Islet ◽  
Proinflammatory Cytokines ◽  
Human Pancreatic Islet ◽  
The Impact ◽  
Splicing Patterns

scholarly journals Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases

2020 ◽  
Vol 10 (2) ◽  
pp. 119 ◽  
Author(s):  
Barbara A. Perez ◽  
Alison Shutterly ◽  
Ying Kai Chan ◽  
Barry J. Byrne ◽  
Manuela Corti
Keyword(s):  
Immune Responses ◽  
Neurodegenerative Diseases ◽  
Targeted Delivery ◽  
Transgene Expression ◽  
Muscular Atrophy ◽  
Canavan Disease ◽  
Clinical Findings ◽  
Promising Alternative ◽  
Gene Therapies ◽  
The Impact

Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.

scholarly journals Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Sunny Kumar ◽  
Daniel Phaneuf ◽  
Pierre Cordeau ◽  
Hejer Boutej ◽  
Jasna Kriz ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Oral Administration ◽  
Neurodegenerative Diseases ◽  
Mouse Models ◽  
Synaptic Function ◽  
Mice Model ◽  
Neurofilament Proteins ◽  
Type Iv ◽  
The Impact ◽  
The Brain

Abstract Background TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown. Methods Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used Ribotag with microarray and proteomic analysis to determine the neuronal translational profile in the mice model of ALS/FTD. Results Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induced autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

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