scholarly journals Homeoprotein ENGRAILED-1 promotes motoneuron survival and motor functions

2019 ◽  
Author(s):  
Stephanie E. Vargas Abonce ◽  
Mélanie Lebœuf ◽  
Kenneth L. Moya ◽  
Alain Prochiantz
Keyword(s):  
Intrathecal Injection ◽  
Spinal Reflex ◽  
Trophic Factor ◽  
Muscle Denervation ◽  
Motoneuron Survival ◽  
Motor Functions ◽  
Autophagy Gene ◽  
Autonomous Activity ◽  
Lateral Sclerosis ◽  
Motoneuron Degeneration

ABSTRACTMotoneuron degeneration leads to skeletal muscle denervation and impaired motor functions, yet the signals involved remain poorly understood. We find that extracellular ENGRAILED-1, a homeoprotein expressed in spinal cord V1 interneurons that synapse on α-motoneurons, has non-cell autonomous activity. Mice heterozygote for Engrailed-1 develop muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation. A single intrathecal injection of ENGRAILED-1 restores innervation, limb strength, extensor reflex and prevents lumbar α-motoneuron death for several months. The autophagy gene p62, which was found to network with Engrailed-1 and amyotrophic lateral sclerosis genes, is misregulated in Engrailed-1 heterozygote mice α-motoneurons and is rescued following ENGRAILED-1 injection. These results identify ENGRAILED-1 as an α-motoneuron trophic factor with long-lasting protective activity.

scholarly journals Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 79 (3) ◽  
pp. 284-295
Author(s):  
Sanjana Shellikeri ◽  
Julia Keith ◽  
Sandra E Black ◽  
Lorne Zinman ◽  
Yana Yunusova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Dna Binding ◽  
Cognitive Deficits ◽  
Regional Distribution ◽  
Neuronal Loss ◽  
Dna Binding Protein ◽  
Motor Functions ◽  
Bulbar Symptoms ◽  
Bulbar Onset ◽  
Lateral Sclerosis

Abstract Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.

Motor neuron disease

2018 ◽  
Author(s):  
Martin R. Turner
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Corticospinal Tract ◽  
Muscular Atrophy ◽  
Muscle Denervation ◽  
Genetic Overlap ◽  
Upper Motor Neurons ◽  
Primary Lateral ◽  
Lateral Sclerosis

Motor neuron disease (MND) is characterized by progressive muscular weakness due to simultaneous degeneration of lower and upper motor neurons (L/UMNs). Involvement of LMNs, arising from the anterior horns of the spinal cord and brainstem, leads to secondary wasting as a result of muscle denervation. Involvement of the UMNs of the motor cortex and corticospinal tract results in spasticity. In ~85% of cases, there is clear clinical involvement of both, and the condition is termed ‘amyotrophic lateral sclerosis’ (ALS; a term often used synonymously with MND). In ~13% of cases, there may be only LMN signs apparent, in which case the condition is termed ‘progressive muscular atrophy’, although such cases have a natural history that is to largely identical to that of ALS. In a very small group of patients (~2%), there are only UMN signs for at least the first 4 years, in which case the condition is termed ‘primary lateral sclerosis’; such cases have a uniformly slower progression. There is clinical, neuropathological, and genetic overlap between MND and some forms of frontotemporal dementia.

scholarly journals Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Félix Leroy ◽  
Boris Lamotte d'Incamps ◽  
Rebecca D Imhoff-Manuel ◽  
Daniel Zytnicki
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Mouse Model ◽  
Postnatal Development ◽  
Superoxide Dismutase 1 ◽  
Critical Test ◽  
Early Postnatal Development ◽  
Contracting Muscle ◽  
Lateral Sclerosis ◽  
Motoneuron Degeneration

In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.

scholarly journals Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Thaddaeus Kwan ◽  
Mohamed Kazamel ◽  
Kristina Thoenes ◽  
Ying Si ◽  
Nan Jiang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Wnt Signaling ◽  
Disease Progression ◽  
Molecular Signature ◽  
Muscle Membrane ◽  
Denervation Atrophy ◽  
Muscle Denervation ◽  
Variable Extent ◽  
End Stage ◽  
Lateral Sclerosis

Abstract Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.

scholarly journals Oral motor functions, speech and communication before a definitive diagnosis of amyotrophic lateral sclerosis

2016 ◽  
Vol 61 ◽  
pp. 97-105 ◽  
Author(s):  
Tanja Makkonen ◽  
Anna-Maija Korpijaakko-Huuhka ◽  
Hanna Ruottinen ◽  
Riitta Puhto ◽  
Kirsi Hollo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Definitive Diagnosis ◽  
Motor Functions ◽  
Oral Motor ◽  
Lateral Sclerosis
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