Age-Dependent Penetrance of Disease in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis

Chiu, Arlene Y.; Zhai, Ping; Canto, Mauro C. Dal; Peters, Theresa M.; Kwon, Young W.; Prattis, S M; Gurney, Mark E.

doi:10.1006/mcne.1995.1027

Cited by 287 publications

(317 citation statements)

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“…Several mouse models of ALS mimic symptoms of the human disease but carry mutations in different genes. In these mouse models, onset of disease symptoms is correlated with degeneration of various brainstem motor nuclei (LaVail et al, 1987;Chiu et al, 1995;Haenggeli and Kato, 2002). These data suggest that branchiomotor and somatomotor neuron loss may play a significant role in the etiology of ALS.…”

Section: Diseases Manifesting Cranial Motor Neuron Dysfunctionmentioning

confidence: 71%

Turning heads: Development of vertebrate branchiomotor neurons

Chandrasekhar

2003

Developmental Dynamics

164

204

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The cranial motor neurons innervate muscles that control eye, jaw, and facial movements of the vertebrate head and parasympathetic neurons that innervate certain glands and organs. These efferent neurons develop at characteristic locations in the brainstem, and their axons exit the neural tube in well-defined trajectories to innervate target tissues. This review is focused on a subset of cranial motor neurons called the branchiomotor neurons, which innervate muscles derived from the branchial (pharyngeal) arches. First, the organization of the branchiomotor pathways in zebrafish, chick, and mouse embryos will be compared, and the underlying axon guidance mechanisms will be addressed. Next, the molecular mechanisms that generate branchiomotor neurons and specify their identities will be discussed. Finally, the caudally directed or tangential migration of facial branchiomotor neurons will be examined. Given the advances in the characterization and analysis of vertebrate genomes, we can expect rapid progress in elucidating the cellular and molecular mechanisms underlying the development of these vital neuronal networks.

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Section: Diseases Manifesting Cranial Motor Neuron Dysfunctionmentioning

confidence: 71%

Turning heads: Development of vertebrate branchiomotor neurons

Chandrasekhar

2003

Developmental Dynamics

164

204

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“…Parallel analysis of the neighboring motor neurons revealed a decline of motor cell number, which became statistically significant at around 100 days of age and occurred in parallel to the appearance of the first signs of motor impairment (Figure 7a). 14,18 Therefore, SGPC formation precedes motor neuron loss and becomes considerable in parallel to degeneration of motor cells and appearance of clinical signs.…”

Section: Resultsmentioning

confidence: 99%

Focal degeneration of astrocytes in amyotrophic lateral sclerosis

et al. 2008

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Astrocytes emerge as key players in motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). Whether astrocytes cause direct damage by releasing toxic factors or contribute indirectly through the loss of physiological functions is unclear. Here we identify in the hSOD1 G93A transgenic mouse model of ALS a degenerative process of the astrocytes, restricted to those directly surrounding spinal motor neurons. This phenomenon manifests with an early onset and becomes significant concomitant with the loss of motor cells and the appearance of clinical symptoms. Contrary to wild-type astrocytes, mutant hSOD1-expressing astrocytes are highly vulnerable to glutamate and undergo cell death mediated by the metabotropic type-5 receptor (mGluR5). Blocking mGluR5 in vivo slows down astrocytic degeneration, delays the onset of the disease and slightly extends survival in hSOD1 G93A transgenic mice. We propose that excitotoxicity in ALS affects both motor neurons and astrocytes, favouring their local interactive degeneration. This new mechanistic hypothesis has implications for therapeutic interventions.

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“…An early study reported a significant loss of lumbar and cervical spinal motor neurons at 90 days of age in SOD1-G93A mice (Chiu et al, 1995). More recent studies have shown, similarly, that significant degeneration and loss of spinal motor neurons occurs by 90-110 days of age in these mice (Guo et al, 2003;Kaspar et al, 2003;Sharp et al, 2005;Niessen et al, 2006).…”

Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 87%

“…An early study found no significant changes in hypoglossal motor neuron number at end-stage (121-125 days of age) (Chiu et al, 1995). However, more recent studies reported significant hypoglossal motor neuron degeneration and loss at 90 days of age (Haenggeli and Kato, 2002;Angenstein et al, 2004).…”

Section: Orolingual Motor Deficitsmentioning

confidence: 98%

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

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Age-Dependent Penetrance of Disease in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis

Cited by 287 publications

References 0 publications

Turning heads: Development of vertebrate branchiomotor neurons

Turning heads: Development of vertebrate branchiomotor neurons

Focal degeneration of astrocytes in amyotrophic lateral sclerosis

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

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