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Journal ArticleDOI

Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development.

TL;DR: Current knowledge of pathogenic commonalities between SMA and ALS is examined, and how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases is discussed.
About: This article is published in European Journal of Medical Genetics.The article was published on 2017-12-01 and is currently open access. It has received 26 citations till now. The article focuses on the topics: SMN1 & Amyotrophic lateral sclerosis.

Summary (2 min read)

INTRODUCTION

  • Motoneuron diseases (MNDs) encompass a group of devastating neurodegenerative disorders characterized by the progressive and selective degeneration of motoneurons in the spinal cord and/or the brain.
  • Interestingly, profilin 1 interacts with SMN and is found within the cytoplasm and Gems of motoneurons (Giesemann et al., 1999).
  • In the present review, the authors will thus take a whole-body approach to discuss the pathological commonalities between SMA and ALS, focusing on skeletal muscle, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuronal excitability and selective motoneuron vulnerability.
  • In addition, the authors will expand on how targeted gene therapy approaches could be exploited to treat shared symptoms in both diseases.

SELECTIVE MOTONEURON VULNERABILITY

  • One of the key commonalities that unite SMA and ALS is the selective vulnerability of motoneurons.
  • Importantly, however, not all populations of motoneurons are equally vulnerable as some are lost very early in disease while others remain relatively intact even at late stages.
  • Identifying common patterns or mechanisms of selective vulnerability between SMA and ALS motoneurons would allow for the development of treatment strategies that may have a wide-reaching potential in several MNDs.
  • Specific restoration of Smn in SMA mice allowed for the correction of SMA motoneuron hyperexcitability and decreased the post-synaptic excitatory potentials (Gogliotti et al., 2012).
  • Thus, while intrinsic hyperexcitability seems to be a hallmark of SMA motoneurons, some controversy still exists for ALS that could be due to differential motoneuron susceptibility, the time course of disease progression and dendritic morphological changes.

NEUROINFLAMMATION AND IMMUNE ORGAN DYSFUNCTION

  • More than 30 years ago, the first signs of astrocytic disturbance were observed in the nervous system of SMA and ALS patients (Brock and McIlwain, 1984).
  • Concordantly, an activated astrocyte phenotype is observed in the spinal cord of SMA mice (McGivern et al., 2013), which is similar to ALS, and takes place before motoneuron soma loss in SMA animals (Dachs et al., 2011; McGivern et al., 2013).
  • In addition to the spleen, abnormal architecture of the thymus is also observed in an SMA mouse model whereby thymic dysplasia is characterized by defective intrathymic T cell development, increased apoptosis as well as increased production of inflammatory cytokines such as IL-6, IL-1 and TNF (Deguise et al., 2017).

WHOLE-BODY METABOLIC DYSHOMEOSTASIS

  • SMA and ALS are both characterized by whole-body metabolic perturbations that if better understood, could lead to the development of therapeutic strategies to restore metabolic homeostasis.
  • The influence of metabolism on SMA and ALS pathogenesis is highlighted by the fact that both dietary and exercise interventions, which are direct modulators of the metabolic state (López-Otín et al., 2016), have been demonstrated to impact disease progression.
  • In severe SMA mice that die pre-weaning, a maternal diet comprising 9% fat (PicoLab20) significantly increased lifespan and improved neuromuscular phenotype compared to a diet of 5.2% fat (Harlan-Teklad 22/5) (Butchbach et al., 2010).
  • In patients, while direct effects of specific diet regimens on disease onset and progression have not been performed, it is clear that nutritional management of SMA patients is critical for overall health.
  • In SMA mice, daily wheel running from post-natal day 10 prolongs survival, prevents motoneuron loss and improves both motor function and cardiac defects (Biondi et al., 2012; Grondard et al., 2005).

TARGETED GENE THERAPIES

  • Because of the lack of effective pharmacological treatments, the possibility of gene therapy has attracted particular attention in the context of fatal MNDs.
  • In addition, although motoneurons display a selective vulnerability in both SMA and ALS, it is evident, as discussed above, that other CNS and non-CNS cell types also have important pathological contributions and optimally should be targeted by gene therapy approaches (Hamilton and Gillingwater, 2013; Imlach et al., 2012; Lalancette-Hebert et al., 2016; Lobsiger and Cleveland, 2007; Simone et al., 2016).
  • These proof-of-principle experiments have prompted a phase I clinical trial in 1-8 months old severe SMA Type I patients with a high-dose administration of the vector (clinicaltrials.gov: NCT02122952).
  • Instead, AAV vectors can be injected directly into the CSF of adult mice and non-human primates to target either motoneurons or astrocytes (Dirren et al., 2014; Meyer et al., 2015; Samaranch et al., 2012).
  • It is therefore critical to identify gene targets that may support the survival and function of diseased motoneurons.

CONCLUSION

  • In the present review, the authors have discussed the cellular and mechanistic pathological similarities between SMA and ALS, two common and devastating MNDs.
  • From the primary motoneuron target to peripheral tissues and systems, understanding the commonalities between both diseases will be of utmost benefit for the development of wide-reaching therapeutic strategies.
  • In addition, identifying key dysregulated pathways may elucidate regulatory networks between cells and tissues, potentially further uncovering primary and secondary causes of disease etiology.
  • Using non-genetic injury-induced models of neurodegeneration, muscle atrophy and neuroinflammation will also provide insight into general vs disease-specific mechanisms.
  • Nevertheless, an integrated combinatorial approach encompassing targeted gene therapy as well as pharmacological, dietary and exercise interventions at various stages during disease progression, will most likely become the optimal strategy to alleviate the CNS and non-CNS defects that arise during the lifetime of SMA and ALS patients.

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Citations
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Journal ArticleDOI
TL;DR: Differential analysis of single microdissected motor neurons and interneurons from human spinal tissue indicated a similar level of proteome coverage, and the two subpopulations of cells were readily differentiated based on single-cell label-free quantification.
Abstract: We report on the combination of nanodroplet sample preparation, ultra-low-flow nanoLC, high-field asymmetric ion mobility spectrometry (FAIMS), and the latest-generation Orbitrap Eclipse Tribrid mass spectrometer for greatly improved single-cell proteome profiling. FAIMS effectively filtered out singly charged ions for more effective MS analysis of multiply charged peptides, resulting in an average of 1056 protein groups identified from single HeLa cells without MS1-level feature matching. This is 2.3 times more identifications than without FAIMS and a far greater level of proteome coverage for single mammalian cells than has been previously reported for a label-free study. Differential analysis of single microdissected motor neurons and interneurons from human spinal tissue indicated a similar level of proteome coverage, and the two subpopulations of cells were readily differentiated based on single-cell label-free quantification.

135 citations

Journal ArticleDOI
TL;DR: The neuroprotective role of melatonin against various N DDs via regulating autophagy is discussed, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.
Abstract: With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

74 citations

Posted ContentDOI
04 Jun 2020-bioRxiv
TL;DR: Differential analysis of single microdissected motor neurons and interneurons from human spinal tissue indicated a similar level of proteome coverage, and the two subpopulations of cells were readily differentiated based on single-cell label-free quantification.
Abstract: We report on the combination of nanodroplet sample preparation, ultra-low-flow nanoLC, high-field asymmetric ion mobility spectrometry (FAIMS), and the latest-generation Orbitrap Eclipse Tribrid mass spectrometer for greatly improved single-cell proteome profiling. FAIMS effectively filtered out singly charged ions for more effective MS analysis of multiply charged peptides, resulting in an average of 1056 protein groups identified from single HeLa cells without MS1-level feature matching. This is 2.3 times more identifications than without FAIMS and a far greater level of proteome coverage for single mammalian cells than has been previously reported for a label-free study. Differential analysis of single microdissected motor neurons and interneurons from human spinal tissue indicated a similar level of proteome coverage, and the two subpopulations of cells were readily differentiated based on single-cell label-free quantification.

64 citations

Book ChapterDOI
TL;DR: This chapter describes the transitions of myofiber types during the progression of muscle atrophy in several pathological states and summarized the ultrastructural and histochemical features characteristic for muscleatrophy in clinical and experimental models for aging, cancer, diabetes and obesity, and heart failure and arrhythmia.
Abstract: Muscle atrophy typically is a direct effect of protein degradation induced by a diversity of pathophysiologic states such as disuse, immobilization, denervation, aging, sepsis, cachexia, glucocorticoid treatment, hereditary muscular disorders, cancer, diabetes and obesity, kidney and heart failure, and others. Muscle atrophy is defined by changes in the muscles, consisting in shrinkage of myofibers, changes in the types of fiber and myosin isoforms, and a net loss of cytoplasm, organelles and overall a protein loss. Although in the literature there are extensive studies in a range of animal models, the paucity of human data is a reality. This chapter is focused on various aspects of muscle wasting and describes the transitions of myofiber types during the progression of muscle atrophy in several pathological states. Clinical conditions associated with muscle atrophy have been grouped based on the fast-to-slow or slow-to-fast fiber-type shifts. We have also summarized the ultrastructural and histochemical features characteristic for muscle atrophy in clinical and experimental models for aging, cancer, diabetes and obesity, and heart failure and arrhythmia.

33 citations

Journal ArticleDOI
22 Feb 2018
TL;DR: The current knowledge on minor spliceosome function is reviewed and its potential pathomechanistic role and impact in neurodegeneration is discussed.
Abstract: Pre-mRNA splicing is an essential step in eukaryotic gene expression. Mutations in cis-acting sequence elements within pre-mRNA molecules or trans-acting factors involved in pre-mRNA processing have both been linked to splicing dysfunction that give rise to a large number of human diseases. These mutations typically affect the major splicing pathway, which excises more than 99% of all introns in humans. However, approximately 700-800 human introns feature divergent intron consensus sequences at their 5' and 3' ends and are recognized by a separate pre-mRNA processing machinery denoted as the minor spliceosome. This spliceosome has been studied less than its major counterpart, but has received increasing attention during the last few years as a novel pathomechanistic player on the stage in neurodevelopmental and neurodegenerative diseases. Here, we review the current knowledge on minor spliceosome function and discuss its potential pathomechanistic role and impact in neurodegeneration.

26 citations


Cites background from "Pathogenic commonalities between sp..."

  • ...Despite the differences in age of onset, disease progression and etiology, FUS-linked and TDP-43-linked ALS and SMA converge with each other [120, 121], and with the minor spliceosome....

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References
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Journal ArticleDOI
04 Mar 1993-Nature
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

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Journal ArticleDOI
13 Jan 1995-Cell
TL;DR: The inverted duplication of a 500 kb element in normal chromosomes is described and the critical region is narrowed to 140 kb within the telomeric region, suggesting that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.

3,401 citations

Journal ArticleDOI
21 Mar 2008-Science
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

2,425 citations

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Q1. What are the contributions in this paper?

In the present review, the authors will examine their current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases.