The role of autophagy in age-related neurodegeneration.
ABSTRACT Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. In many cases, these proteinaceous deposits are composed of ubiquitin conjugates, suggesting a failure in the clearance of proteins targeted for degradation. The 2 principal routes of intracellular protein catabolism are the ubiquitin proteasome system and the autophagy-lysosome system (autophagy). Both of these degradation pathways have been implicated as playing important roles in the pathogenesis of neurodegenerative disease. Here we describe autophagy and review the evidence suggesting that impairment of autophagy contributes to the initiation or progression of age-related neurodegeneration. We also review recent evidence indicating that autophagy may be exploited to remove toxic protein species, suggesting novel strategies for therapeutic intervention for a class of diseases for which no effective treatments presently exist.
SourceAvailable from: Yasir H Qureshi[Show abstract] [Hide abstract]
ABSTRACT: Many neurodegenerative disorders are characterized by the aberrant accumulation of aggregate-prone proteins. Alzheimer's disease (AD) is associated with the buildup of β-amyloid peptides and tau, which aggregate into extracellular plaques and neurofibrillary tangles, respectively. Multiple studies have linked dysfunctional intracellular degradation mechanisms with AD pathogenesis. One such pathway is the autophagy-lysosomal system, which involves the delivery of large protein aggregates/inclusions and organelles to lysosomes through the formation, trafficking, and degradation of double-membrane structures known as autophagosomes. Converging data suggest that promoting autophagic degradation, either by inducing autophagosome formation or enhancing lysosomal digestion, provides viable therapeutic strategies. In this review, we discuss compounds that can augment autophagic clearance and may ameliorate disease-related pathology in cell and mouse models of AD. Canonical autophagy induction is associated with multiple signaling cascades; on the one hand, the best characterized is mammalian target of rapamycin (mTOR). Accordingly, multiple mTOR-dependent and mTOR-independent drugs that stimulate autophagy have been tested in preclinical models. On the other hand, there is a growing list of drugs that can enhance the later stages of autophagic flux by stabilizing microtubule-mediated trafficking, promoting lysosomal fusion, or bolstering lysosomal enzyme function. Although altering the different stages of autophagy provides many potential targets for AD therapeutic interventions, it is important to consider how autophagy drugs might also disturb the delicate balance between autophagosome formation and lysosomal degradation.Journal of the American Society for Experimental NeuroTherapeutics 11/2014; 12(1). DOI:10.1007/s13311-014-0320-z · 3.88 Impact Factor
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ABSTRACT: A common feature of many neurodegenerative diseases is the accumulation of toxic proteins that disrupt vital cellular functions. Degradative pathways such as autophagy play an important protective role in breaking down misfolded and long-lived proteins. Neurons are particularly vulnerable to defects in these pathways, but many of the details regarding the link between autophagy and neurodegeneration remain unclear. We previously found that temperature-sensitive (ts) paralytic mutants in Drosophila are enriched for those exhibiting age-dependent neurodegeneration. Here we show that one of these mutants, comatose (comt), in addition to locomotor defects, displays shortened lifespan and progressive neurodegeneration, including loss of dopaminerigic (DA) neurons. comt encodes N-ethyl-maleimide sensitive fusion protein (NSF1), which has a well-documented role in synaptic transmission. However, the neurodegenerative phenotypes we observe in comt mutants do not appear to depend on defects in synaptic transmission, but rather from their inability to sustain autophagy under stress, due at least in part to a defect in trafficking of lysosomal proteases such as Cathepsin-L. Conversely, over-expression of NSF1 rescues α-synuclein-induced toxicity of DA neurons in a model of Parkinson's Disease. Our results demonstrate a neuroprotective role for NSF1 that involves mediation of fusion events crucial for degradative pathways such as autophagy, providing greater understanding of cellular dysfunctions common to several neurodegenerative diseases. Copyright © 2014, The Genetics Society of America.Genetics 12/2014; 199(2). DOI:10.1534/genetics.114.172403 · 4.87 Impact Factor
Article: Mitophagy and heart failure[Show abstract] [Hide abstract]
ABSTRACT: Cardiac mitochondria are responsible for generating energy in the form of ATP through oxidative phosphorylation and are crucial for cardiac function. Mitochondrial dysfunction is a major contributor to loss of myocytes and development of heart failure. Myocytes have quality control mechanisms in place to ensure a network of functional mitochondria. Damaged mitochondria are degraded by a process called mitochondrial autophagy, or mitophagy, where the organelle is engulfed by an autophagosome and subsequently delivered to a lysosome for degradation. Evidence suggests that mitophagy is important for cellular homeostasis, and reduced mitophagy leads to inadequate removal of dysfunctional mitochondria. In this review, we discuss the regulation of mitophagy and the emerging evidence of the cardioprotective role of mitophagy. We also address the prospect of therapeutically targeting mitophagy to treat patients with cardiovascular disease.Journal of Molecular Medicine 01/2015; 93(3). DOI:10.1007/s00109-015-1254-6 · 4.74 Impact Factor