scholarly journals Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease

2021 ◽  
Vol 118 (50) ◽  
pp. e2107389118
Author(s):  
Miriam Scarpa ◽  
Colin Molloy ◽  
Laura Jenkins ◽  
Bethany Strellis ◽  
Rebecca F. Budgett ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Progression ◽  
Muscarinic Acetylcholine Receptor ◽  
Memory Loss ◽  
Normal Animal ◽  
Genetically Engineered ◽  
Receptor Phosphorylation ◽  
M1 Receptor ◽  
M1 Muscarinic ◽  
Preclinical Animal Models

There are currently no treatments that can slow the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD). There is, however, a growing body of evidence that activation of the M1 muscarinic acetylcholine receptor (M1-receptor) can not only restore memory loss in AD patients but in preclinical animal models can also slow neurodegenerative disease progression. The generation of an effective medicine targeting the M1-receptor has however been severely hampered by associated cholinergic adverse responses. By using genetically engineered mouse models that express a G protein–biased M1-receptor, we recently established that M1-receptor mediated adverse responses can be minimized by ensuring activating ligands maintain receptor phosphorylation/arrestin-dependent signaling. Here, we use these same genetic models in concert with murine prion disease, a terminal neurodegenerative disease showing key hallmarks of AD, to establish that phosphorylation/arrestin-dependent signaling delivers neuroprotection that both extends normal animal behavior and prolongs the life span of prion-diseased mice. Our data point to an important neuroprotective property inherent to the M1-receptor and indicate that next generation M1-receptor ligands designed to drive receptor phosphorylation/arrestin-dependent signaling would potentially show low adverse responses while delivering neuroprotection that will slow disease progression.

scholarly journals Phosphorylation of the M1 muscarinic acetylcholine receptor mediates protection in neurodegenerative disease

2021 ◽  
Author(s):  
Miriam Scarpa ◽  
Colin Molloy ◽  
Laura Jenkins ◽  
Gonzalo Tejeda ◽  
Mario Rossi ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Disease Progression ◽  
Acetylcholine Receptor ◽  
Muscarinic Acetylcholine Receptor ◽  
Genetically Engineered ◽  
Receptor Phosphorylation ◽  
Muscarinic Acetylcholine ◽  
M1 Receptor ◽  
M1 Muscarinic Acetylcholine Receptor ◽  
M1 Muscarinic

AbstractThere are currently no treatments that can slow the progression of neurodegenerative diseases such as Alzheimer’s disease (AD). There is, however, a growing body of evidence that activation of the M1 muscarinic acetylcholine receptor (M1-receptor) can not only restore memory loss in AD patients, but in preclinical animal models can also slow neurodegenerative disease progression. The generation of an effective medicine targeting the M1-receptor has however been severely hampered by associated cholinergic adverse responses. By using genetically engineered mouse models that express a G protein-biased M1-receptor, we recently established that M1-receptor mediated adverse responses can be minimised by ensuring activating ligands maintain receptor phosphorylation/arrestin-dependent signalling. Here, we use these same genetic models in concert with murine prion disease, a terminal neurodegenerative disease showing key hallmarks of AD, to establish that phosphorylation/arrestin-dependent signalling delivers neuroprotection that both extends normal animal behaviour and prolongs the life span of prion diseased mice. Our data point to an important neuroprotective property inherent to the M1-receptor and indicate that next generation M1-receptor ligands designed to drive receptor phosphorylation/arrestin-dependent signalling would potentially show low adverse responses whilst delivering neuroprotection that will slow disease progression.

scholarly journals Activation of M1 muscarinic receptors reduce pathology and slow progression of neurodegenerative disease.

2021 ◽  
Author(s):  
Louis Dwomoh ◽  
Mario Rossi ◽  
Miriam Scarpa ◽  
Elham Khajehali ◽  
Colin Molloy ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Synaptic Proteins ◽  
Normal Behaviour ◽  
M1 Receptor ◽  
Slow Progression ◽  
M1 Receptors ◽  
M1 Muscarinic ◽  
The Brain ◽  
M1 Muscarinic Receptors ◽  
Human Neurodegenerative Disease

The most prevalent types of dementias, including Alzheimer's disease, are those that are propagated via the spread of 'prion-like' misfolded proteins. Despite considerable effort, no treatments are available to slow or stop the progression of these dementias. Here, we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which we show here displays many of the pathological, behavioural and biochemical hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimer′s disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has the potential to reduce the severity of neurodegenerative diseases caused by the ″prion-like″ propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.

scholarly journals Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction

2016 ◽  
Vol 113 (16) ◽  
pp. 4524-4529 ◽  
Author(s):  
Sophie J. Bradley ◽  
Coen H. Wiegman ◽  
Max Maza Iglesias ◽  
Kok Choi Kong ◽  
Adrian J. Butcher ◽  
...  
Keyword(s):  
Lung Function ◽  
Signaling Pathways ◽  
G Protein ◽  
Physiological Responses ◽  
Muscarinic Acetylcholine Receptor ◽  
Smooth Muscle Contraction ◽  
Genetically Engineered ◽  
Receptor Phosphorylation ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR–biased ligands with important implications for drug discovery.

scholarly journals 125 Short Duration Monoballismus

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 79-80
Author(s):  
Davinder Dhillon ◽  
Priya Batta ◽  
Alan R. Hirsch
Keyword(s):  
Short Duration ◽  
Parietal Lobe ◽  
Focal Epilepsy ◽  
Memory Loss ◽  
Low Frequency ◽  
Normal Animal ◽  
Conversion Disorder ◽  
Huntington's Chorea ◽  
Study Objective ◽  
Alien Hand Syndrome

AbstractStudy ObjectiveWhile monoballismus has been reported to be associated with hemorrhagic lesions in the subthalamic nucleus (Ohnishi, 2009) and multiple sclerosis (MS) (Rosa, 2011), the duration has been reported to be at least six days (Soysal, 2012). A patient with epochs of monoballismus lasting for 45 minutes is presented.MethodsCase Study: A 57 year old right handed female with attention deficit hereditary disorder predominantly inattentive on amphetamine sulphate, presented with two years of memory loss. For instance, after ordering food in restaurants, by the time the food arrives, she could not recall what she ordered. At the onset of this symptom, she noted three epochs of her left arm jerking for 45 minutes. The jerking would begin with low amplitude and low frequency and rapidly progress to the forearm and arm of greater magnitude and low frequency. With her right hand she would try to hold down her left arm without success. There was no associated paresis, sensory phenomena, headaches, dizziness, presyncope, loss of consciousness, or strong emotions. She admitted to frequent jamais vu.ResultsAbnormalities: Neurological Examination: Mental Status Examination: Memory: Immediate Recall: 5 digits forward and 2 digits backwards. Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test 8 (hyposmia). CN XII: tongue tremor on protrusion. Motor Examination: Drift Test: positive right pronator drift. Gait Examination: Tandem Gait: unstable. Reflexes: 0-1 throughout. Neuropsychiatric Examination: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 15 (normal). Clock Drawing Test: 3 (abnormal). Center for Neurologic Study Lability Scale: 16 (pseudobulbar affect). Other: MRI with and without infusion: normal.ConclusionTransient tonic-clonic movements of one limb have been described with focal epilepsy associated with diabetic non-ketotic hyperglycemia (Grant, 1985). A metabolic abnormality such as transient hypoglycemia or hyperkalemia can cause a focal dystonia (Soysal, 2012), which theoretically could manifest with monoballismus. This could be a somatic manifestation of underlying conflict, conversion disorder, or as a result of a physical manifestation of panic attack with hyperventilation and tetany (Mihai, 2008). This may be the first manifestation of a generalized cerebral disorder associated with chorea or ballismus such as Wilson’s disease, or Huntington’s Chorea (Mihai, 2008). It is possible that this is a variant of Alien Hand Syndrome with parietal lobe involvement (Shrestha, 2015). But this is unlikely given the absence of hemineglect or hemiagnosia. It is possible that amphetamines may have induced a monochorea. Chronic amphetamine use has been demonstrated to cause chorea (Klawans, 1974) and it theoretically could have caused ballismus movements in this case. In patients who present with short duration monoballismus, evaluation for subthalamic nuclei function, seizure disorders and other origins of ballismus are warranted.Funding AcknowledgementsSmell & Taste Treatment and Research Foundation

scholarly journals Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma

Pancreas ◽  
2018 ◽  
Vol 47 (7) ◽  
pp. 856-863 ◽  
Author(s):  
Jami L. Saloman ◽  
Aatur D. Singhi ◽  
Douglas J. Hartman ◽  
Daniel P. Normolle ◽  
Kathryn M. Albers ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Progression ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Nerve Growth

scholarly journals Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders

2018 ◽  
Vol 19 (11) ◽  
pp. 3581 ◽  
Author(s):  
Heike Rebholz ◽  
Eitan Friedman ◽  
Julia Castello
Keyword(s):  
Executive Function ◽  
Food Intake ◽  
Serotonin Receptor ◽  
Current Knowledge ◽  
Memory Loss ◽  
Brain Regions ◽  
Brain Disorders ◽  
Protein Levels ◽  
Preclinical Animal Models ◽  
Mood Depression

The serotonin 4 receptor, 5-HT4R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer’s disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT4R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT4R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT4R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT4R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels.

Sign in / Sign up

Export Citation Format

Share Document