The Molecular Clock and Neurodegenerative Disease: A Stressful Time

Abstract

Circadian rhythm dysfunction occurs in both common and rare neurodegenerative diseases. This dysfunction manifests as sleep cycle mistiming, alterations in body temperature rhythms, and an increase in symptomatology during the early evening hours known as Sundown Syndrome. Disruption of circadian rhythm homeostasis has also been implicated in the etiology of neurodegenerative disease. Indeed, individuals exposed to a shifting schedule of sleep and activity, such as health care workers, are at a higher risk. Thus, a bidirectional relationship exists between the circadian system and neurodegeneration. At the heart of this crosstalk is the molecular circadian clock, which functions to regulate circadian rhythm homeostasis. Over the past decade, this connection has become a focal point of investigation as the molecular clock offers an attractive target to combat both neurodegenerative disease pathogenesis and circadian rhythm dysfunction, and a pivotal role for neuroinflammation and stress has been established. This review summarizes the contributions of molecular clock dysfunction to neurodegenerative disease etiology, as well as the mechanisms by which neurodegenerative diseases affect the molecular clock.

Alternative Splicing Mechanisms Underlying Opioid-Induced Hyperalgesia

“…While Dbp and Ciart were over-expressed at the isoform and gene levels [10], the transcript isoform from Arntl was under-expressed in OIH relative to control mice (Table 2), in agreement with the gene-level profile [10]. The role of alternative splicing on biological timing, and stress response has been reported in multiple species [67].…”

Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease

“…Since key circadian rhythm genes were changed in a key neuronal population in our study, and in several others (Carter et al, 2021), we asked if circadian rhythm regulation becomes more vulnerable to external disturbances in RML, accelerating disease progression. A common alteration of circadian rhythmicity in humans is when crossing different time zones, the poor adaptation referred to as jet lag (JL).…”

“…These differences are related to RML and not time of death, as the latter was controlled for in our experimental design. Remarkably, circadian rhythm genes are commonly dysregulated in neurodegenerative diseases (Carter, Justin, Gulick, & Gamsby, 2021). Many of the downregulated genes normally suppress Arntl expression, potentially explaining its upregulation.…”

“…GABAergic neurons prominently modulated their translatomes for the circadian rhythm pathway. Since circadian rhythm genes have been associated with neurodegeneration (Carter et al, 2021; Fifel & Videnovic, 2020; Leng, Musiek, Hu, Cappuccio, & Yaffe, 2019), we tested whether interfering with the circadian rhythm system would worsen disease. Theta in RML mice measured two weeks after the last PA tended to be different between JL and undisturbed control mice but was not significant.…”

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

“…Furthermore, Bmal1 depletion from astrocytes leads to motor and cognitive alterations and shortens the lifespan in transgenic mice [74,75]. Considering that circadian arrhythmias can contribute to the development of neurological conditions and recognize symptoms of different neurodegenerative diseases [76], we speculate that astrocytes might be the primary source of impairment. Further investigations are, however, required to dissect the contribution of inflammation to circadian rhythm alteration and, therefore, to develop a suitable therapeutic intervention.…”