Circadian Rhythm Dysfunction Accelerates Disease Progression in a Mouse Model With Amyotrophic Lateral Sclerosis

Huang, Zifeng; Liu, Qiang; Yu, Peng; Dai, Jiaying; Xie, Youna; Chen, Wei-Neng; Long, Simei; Pei, Zhong; Su, Huanxing; Yao, Xiaoli

doi:10.3389/fneur.2018.00218

Cited by 25 publications

(17 citation statements)

References 54 publications

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“…Our recent report of dysregulated circadian regulation of the GC-KLF15-BCAA pathway in SMA mice ( 37 ) further supports a functional relationship between this neuromuscular disease and systemic disruption of peripheral core clock and circadian rhythm genes. As circadian defects have been reported in models of other neuromuscular disorders such as collagen VI myopathy ( 61 ) and amyotrophic lateral sclerosis ( 62 ), our results may also reflect a more general relationship between circadian homeostasis and neuromuscular health.…”

Section: Discussionsupporting

confidence: 71%

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter

Koch

Betts

et al. 2018

Human Molecular Genetics

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Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn−/−;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.

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Section: Discussionsupporting

confidence: 71%

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Walter

Koch

Betts

et al. 2018

Human Molecular Genetics

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“…In SOD1G93A mice have been observed sleep-related EEG/EMG abnormalities that increase with age [30]. Additionally, always in SOD1G93A mice, melatonin has been shown to increase survival [31] while light-induced disruption of circadian rhythm anticipated disease onset and reduced survival [32]. Our findings, though not measuring sleep directly, agree with a surge of rest fragmentation in both male and female SOD1G93A mice at the symptomatic stage and an indication of early onset of such disturbances.…”

Section: Discussionsupporting

confidence: 82%

A non-invasive digital biomarker for the detection of rest disturbances in the SOD1G93A mouse model of ALS

Golini

Rigamonti²,

Iannello³

et al. 2019

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that affects both central and peripheral nervous system, leading to the degeneration of motor neurons, which eventually results in muscle atrophy, paralysis and death. Sleep disturbances are common in patients with ALS, leading to even further deteriorated quality of life. Investigating methods to potentially assess sleep and rest disturbances in animal models of ALS is thus of crucial interest.We used an automated home cage monitoring system (DVC ® ) to capture activity patterns that can potentially be associated with sleep and rest disturbances and thus to the progression of ALS in the SOD1G93A mouse model. DVC ® enables non-intrusive 24/7 long term animal activity monitoring, which we assessed together with body weight decline and neuromuscular function deterioration measured by grid hanging and grip strength tests in male and female mice from 7 until 24 weeks of age.We show that as the ALS progresses over time in SOD1G93A mice, activity patterns during day time start becoming irregular, with frequent activity bouts that are neither observed in control mice nor in SOD1G93A at a younger age. The increasing irregularities of activity patterns during day time are quantitatively captured by designing a novel digital biomarker, referred to as Rest Disturbance Index (RDI). We show that RDI is a robust measure capable of detecting rest/sleeprelated disturbances during the disease progression earlier than conventional methods, such as the grid hanging test. Moreover RDI highly correlates with grid hanging and body weight decline, especially in males.The non-intrusive long-term continuous monitoring of animal activity enabled by DVC ® has been instrumental in discovering activity patterns potentially correlated with sleep and rest disturbances in the SOD1G93A mouse model of the ALS disease.

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“…In SOD1G93A mice have been observed sleep-related EEG/EMG abnormalities that increase with age ( Liu et al, 2015 ). Additionally, always in SOD1G93A mice, melatonin has been shown to increase survival ( Weishaupt et al, 2006 ) while light-induced disruption of circadian rhythm anticipated disease onset and reduced survival ( Huang et al, 2018 ). Our findings, though not measuring sleep directly, suggest a surge of rest fragmentation in both male and female SOD1G93A mice at the symptomatic stage.…”

Section: Discussionmentioning

confidence: 99%

A Non-invasive Digital Biomarker for the Detection of Rest Disturbances in the SOD1G93A Mouse Model of ALS

Golini

Rigamonti²,

Iannello³

et al. 2020

Front. Neurosci.

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Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that affects both central and peripheral nervous system, leading to the degeneration of motor neurons, which eventually results in muscle atrophy, paralysis, and death. Sleep disturbances are common in patients with ALS, leading to even further deteriorated quality of life. Investigating methods to potentially assess sleep and rest disturbances in animal models of ALS is thus of crucial interest. We used an automated home cage monitoring system (DVC ® ) to capture irregular activity patterns that can potentially be associated with sleep and rest disturbances and thus to the progression of ALS in the SOD1G93A mouse model. DVC ® enables non-intrusive 24/7 long term animal activity monitoring, which we assessed together with body weight decline and neuromuscular function deterioration measured by grid hanging and grip strength tests in male and female mice from 7 until 24 weeks of age. We show that as the ALS progresses over time in SOD1G93A mice, activity patterns start becoming irregular, especially during day time, with frequent activity bouts that are neither observed in control mice nor in SOD1G93A at a younger age. The increasing irregularities of activity pattern are quantitatively captured by designing a novel digital biomarker, referred to as Regularity Disruption Index (RDI). We show that RDI is a robust measure capable of detecting home cage activity patterns that could be related to rest/sleep-related disturbances during the disease progression. Moreover, the RDI rise during the early symptomatic stage parallels grid hanging and body weight decline. The non-intrusive long-term continuous monitoring of animal activity enabled by DVC ® has been instrumental in discovering novel activity patterns potentially correlated, once validated, with sleep and rest disturbances in the SOD1G93A mouse model of the ALS disease.

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Circadian Rhythm Dysfunction Accelerates Disease Progression in a Mouse Model With Amyotrophic Lateral Sclerosis

Cited by 25 publications

References 54 publications

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice

A non-invasive digital biomarker for the detection of rest disturbances in the SOD1G93A mouse model of ALS

A Non-invasive Digital Biomarker for the Detection of Rest Disturbances in the SOD1G93A Mouse Model of ALS

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