Spinale Muskelatrophien: Klinik und Therapie

2018 ◽  
Vol 86 (09) ◽  
pp. 543-550
Author(s):  
Maggie C. Walter ◽  
Anne Julia Stauber
Keyword(s):  
Motor Neuron ◽  
Spinale Muskelatrophie ◽  
Neurodegenerative Erkrankung ◽  
Smn Protein ◽  
Wenn Sich

ZusammenfassungDie spinale Muskelatrophie (SMA) ist eine fortschreitende autosomal rezessive Motoneuronerkrankung mit einer Inzidenz von 1 in 10.000 Lebendgeburten, die durch den Verlust des Survial Motor Neuron 1 Gens (SMN1) verursacht wird, und stellt die häufigste neurodegenerative Erkrankung im Kindesalter dar. Mit besserem Verständnis der molekularen Basis der SMA in den letzten beiden Jahrzehnten verdichtete sich der Fokus therapeutischer Entwicklungen auf eine Erhöhung des Anteils an funktionsfähigem SMN Protein, entweder durch Einschluss von Exon 7 in SNM2 Transkripte, Erhöhung der SMN2 Genexpression, oder durch direkten Genersatz von SMN1. Auch wenn sich die therapeutischen Möglichkeiten bei SMA mit den zahlreichen neuen Therapieansätzen deutlich verbessert haben, bleiben dennoch zahlreiche Fragen wie der richtige Zeitpunkt für eine optimale therapeutische Intervention ungeklärt. Bestimmend für den Therapieerfolg wird die frühzeitige Erkennung der Erkrankung sein – es ist davon auszugehen, dass ein früher, nach Möglichkeit präsymptomatischer Therapiebeginn das Outcome im Vergleich zu einem späteren Therapiebeginn entscheidend verbessert. Ziel muss daher die präsymptomatische Diagnosestellung durch ein molekulargenetisches Neugeborenenscreening auf SMA sein, um eine Behandlung vor dem Untergang der Motoneurone einleiten zu können.

Neue Therapien der spinalen Muskelatrophie

2018 ◽  
Vol 45 (08) ◽  
pp. 617-624 ◽  
Author(s):  
Maggie Walter ◽  
Benedikt Schoser
Keyword(s):  
Motor Neuron ◽  
Survival Motor Neuron ◽  
Spinale Muskelatrophie ◽  
Neurodegenerative Erkrankung ◽  
Spezifische Therapie ◽  
Smn Protein

ZusammenfassungDie 5q-assoziierte spinale Muskelatrophie (5q-SMA) ist eine progressive autosomal rezessive Motoneuronerkrankung mit einer Inzidenz von 1 in 10 000 Geburten. Die 5q-SMA ist durch den Verlust des Survival Motor Neuron 1 Gens (SMN1) verursacht. Sie stellt die häufigste neurodegenerative Erkrankung im Kindesalter dar. 126 Jahre nach der Erstbeschreibung durch Hofmann kam es 2017 zur Erstzulassung einer spezifischen Therapie der SMA in Deutschland. Durch eine Erhöhung des Anteils an funktionsfähigem SMN-Protein, die entweder durch Einschluss von Exon 7 in SNM2-Transkripte, Erhöhung der SMN2-Genexpression oder durch direkten Genersatz von SMN1 erzielt werden kann, ist eine spezifische Therapie nun möglich geworden. Zahlreiche Fragen – was ist der Zeitpunkt für eine optimale therapeutische Intervention, welche therapeutische Maßnahme ist die geeignetste, was sind mögliche Wechselwirkungen gentherapeutischer Maßnahmen – bleiben derzeit noch ungeklärt. Die Kenntnis der klinischen Symptome der SMA und das Wissen um eine spezifische Therapie werden diese bislang als unbehandelbar geltende Erkrankung neu in den medizinischen Fokus bringen, sodass ein früher, nach Möglichkeit präsymptomatischer Therapiebeginn das Outcome im Vergleich zu einem späteren Therapiebeginn entscheidend verbessern wird.

scholarly journals Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Maximilian Paul Thelen ◽  
Brunhilde Wirth ◽  
Min Jeong Kye
Keyword(s):  
Protein Synthesis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Complex I ◽  
Energy Homeostasis ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Translational Initiation ◽  
Protein Levels ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA is caused by reduced survival motor neuron (SMN) protein levels due to biallelic deletions or mutations in the SMN1 gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed, including RNA processing, protein synthesis, metabolic defects, and mitochondrial function. Dysfunctional mitochondria can harm cells by decreased ATP production and increased oxidative stress due to elevated cellular levels of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA pathology. Here, we report, based on proteome analysis, that SMA motor neurons show disturbed energy homeostasis due to dysfunction of mitochondrial complex I. This results in a lower basal ATP concentration and higher ROS production that causes an increase of protein carbonylation and impaired protein synthesis in SMA motor neurons. Counteracting these cellular impairments with pyruvate reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis at the translational initiation step, which is impaired in SMA. As many neuropathies share pathological phenotypes such as dysfunctional mitochondria, excessive ROS, and impaired protein synthesis, our findings suggest new molecular interactions among these pathways. Additionally, counteracting these impairments by reducing ROS and increasing ATP might be beneficial for motor neuron survival in SMA patients.

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

scholarly journals Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

2018 ◽  
Vol 29 (2) ◽  
pp. 96-110 ◽  
Author(s):  
Kelsey M. Gray ◽  
Kevin A. Kaifer ◽  
David Baillat ◽  
Ying Wen ◽  
Thomas R. Bonacci ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Protein Isoforms ◽  
Survival Motor Neuron Protein ◽  
Protein Levels ◽  
Motor Neuron Protein ◽  
Smn Protein ◽  
Oligomerization Domain

SMN protein levels inversely correlate with the severity of spinal muscular atrophy. The SCFSlmbE3 ligase complex interacts with a degron embedded within the C-terminal self-oligomerization domain of SMN. The findings elucidate a model whereby accessibility of the SMN degron is regulated by self-multimerization.

scholarly journals Identification of Novel Compounds That Increase SMN Protein Levels Using an Improved SMN2 Reporter Cell Assay

2012 ◽  
Vol 17 (4) ◽  
pp. 481-495 ◽  
Author(s):  
Jonathan J. Cherry ◽  
Matthew C. Evans ◽  
Jake Ni ◽  
Gregory D. Cuny ◽  
Marcie A. Glicksman ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neurodegenerative Disorder ◽  
Muscular Atrophy ◽  
Full Length ◽  
Reporter Cell ◽  
Protein Levels ◽  
Smn2 Gene ◽  
Smn Protein ◽  
Neuron Function ◽  
Survival Of Motor Neuron

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that is characterized by progressive loss of motor neuron function. It is caused by the homozygous loss of the SMN1 ( survival of motor neuron 1) gene and a decrease in full-length SMN protein. SMN2 is a nearly identical homolog of SMN1 that, due to alternative splicing, expresses predominantly truncated SMN protein. SMN2 represents an enticing therapeutic target. Increasing expression of full-length SMN from the SMN2 gene might represent a treatment for SMA. We describe a newly designed cell-based reporter assay that faithfully and reproducibly measures full-length SMN expression from the SMN2 gene. This reporter can detect increases of SMN protein by an array of compounds previously shown to regulate SMN2 expression and by the overexpression of proteins that modulate SMN2 splicing. It also can be used to evaluate changes at both the transcriptional and splicing level. This assay can be a valuable tool for the identification of novel compounds that increase SMN2 protein levels and the optimization of compounds already known to modulate SMN2 expression. We present here preliminary data from a high-throughput screen using this assay to identify novel compounds that increase expression of SMN2.

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