Autophagy in the Pathogenesis of Disease

Many late-onset neurodegenerative diseases, including Parkinson's disease and Huntington's disease, are associated with the formation of intracellular aggregates by toxic proteins. It is therefore crucial to understand the factors that regulate the steady-state levels of these 'toxins', at both the synthetic and degradation stages. The degradation pathways acting on such aggregate-prone cytosolic proteins include the ubiquitin-proteasome system and macroautophagy. Dysfunction of the ubiquitin-proteasome or macroautophagy pathways might contribute to the pathology of various neurodegenerative conditions. However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases.

The roles of intracellular protein-degradation pathways in neurodegeneration

(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.

https://www.physiology.org/doi/pdf/10.1152/physrev.00030.2009

Regulation of Mammalian Autophagy in Physiology and Pathophysiology

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anat...

Pathophysiology of Sleep Apnea

Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.

Decoding ALS: from genes to mechanism

Impaired axonal transport in motor neurons has been proposed as a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lower motor neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain. Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease.

/pdf/mutant-dynactin-in-motor-neuron-disease-3m12s0vx5w.pdf

Mutant dynactin in motor neuron disease.

Disruption of axonal transport has been implicated in the mechanism of frontotemporal dementia,1 polyglutamine diseases,2,3 and amyotrophic lateral sclerosis.4,5 The importance of the dynein–dynactin microtubule motor proteins, which mediate retrograde axonal transport, has been further emphasized by recent studies showing that mutation or disruption of these motor proteins leads to late-onset motor neuron disease in mice.6,7 We recently reported on a family in which a G59S missense mutation in the p150Glued subunit of dynactin is associated with an autosomal dominant form of motor neuron disease.8 In this study, we delineate the unique clinical, electrophysiological, and pathological effects of this mutation.

Distal spinal and bulbar muscular atrophy caused by dynactin mutation.

During swallowing, airway protection is achieved in part by laryngeal elevation. Although multiple muscles are normally active during laryngeal elevation, neuromuscular stimulation of select muscle...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00406.2002

Laryngeal elevation achieved by neuromuscular stimulation at rest.

Objectives To determine the effects of neuromuscular stimulation (NS) of the genioglossus muscle on hypopharyngeal airway size



Study Design Fourteen consecutively recruited healthy volunteers underwent percutaneous electrical NS of the genioglossus muscle



Methods Bipolar hooked wires were inserted percutaneously into the genioglossus muscle and used for NS The anterior–posterior diameter of the hypopharynx was measured at the level of the superior edge of the epiglottis at baseline and during NS from recorded video endoscopic examinations



Results NS of the genioglossus muscle resulted in a significant increase in the diameter of the hypopharyngeal airway (P = 002) compared with baseline, ranging from a 33% to 284% increase in airway diameter Three of the 14 patients demonstrated modest decreases in airway diameter, likely the result of faulty electrode placement in surrounding tongue retrusive muscles



Conclusions NS of the genioglossus muscle was effective in increasing the hypopharyngeal airway and may provide a useful alternative to direct stimulation of the hypoglossal nerve with a nerve cuff electrode in the development of neuroprosthetic treatments for obstructive sleep apnea

The Effect of Neuromuscular Stimulation of the Genioglossus on the Hypopharyngeal Airway

Hyolaryngeal elevation is essential for airway protection during swallowing and is mainly a reflexive response to oropharyngeal sensory stimulation. Targeted intramuscular electrical stimulation can elevate the resting larynx and, if applied during swallowing, may improve airway protection in dysphagic patients with inadequate hyolaryngeal motion. To be beneficial, patients must synchronize functional electrical stimulation (FES) with their reflexive swallowing and not adapt to FES by reducing the amplitude or duration of their own muscle activity. We evaluated the ability of nine healthy adults to manually synchronize FES with hyolaryngeal muscle activity during discrete swallows, and tested for motor adaptation. Hooked-wire electrodes were placed into the mylo- and thyrohyoid muscles to record electromyographic activity from one side of the neck and deliver monopolar FES for hyolaryngeal elevation to the other side. After performing baseline swallows, volunteers were instructed to trigger FES with a thumb switch in synchrony with their swallows for a series of trials. An experimenter surreptitiously disabled the thumb switch during the final attempt, creating a foil. From the outset, volunteers synchronized FES with the onset of swallow-related thyrohyoid activity (∼225 ms after mylohyoid activity onset), preserving the normal sequence of muscle activation. A comparison between average baseline and foil swallows failed to show significant adaptive changes in the amplitude, duration, or relative timing of activity for either muscle, indicating that the central pattern generator for hyolaryngeal elevation is immutable with short term stimulation that augments laryngeal elevation during the reflexive, pharyngeal phase of swallowing.

https://www.physiology.org/doi/pdf/10.1152/jn.00025.2005

Eric A. Mann

Papers

Mutant dynactin in motor neuron disease.

Distal spinal and bulbar muscular atrophy caused by dynactin mutation.

Laryngeal elevation achieved by neuromuscular stimulation at rest.

The Effect of Neuromuscular Stimulation of the Genioglossus on the Hypopharyngeal Airway

Self-Triggered Functional Electrical Stimulation During Swallowing