Biomedical Sciences Neuroscience. Current Topics in Neurotoxicity Free Preview. Evaluates the interplay between autophagy and toxicity in neurodegenerative disease Contains contributions from an international group of experts Addresses the major diseases: Alzheimer's, Parkinson's, Huntington's see more benefits. Buy eBook. Buy Hardcover. Buy Softcover. FAQ Policy.
Moreover, curcumin, a diaryheptanoid possessing antioxidant properties, ameliorates the neurotoxicity in the A53T SNCA cell model of PD through recovery of macroautophagy Jiang et al. Because the basal level of autophagy is essentially required for maintaining neuronal homeostasis, enhancement of basal autophagy is explored as a therapeutic target.
Overexpression of RAB1A, a key regulator of intracellular membrane trafficking and autophagosome assembly, was shown to partially improve motor deficits in SNCA-expressing dopaminergic neurons Coune et al. Thus, these findings provide a significant role of autophagy in the pathogenesis of PD. Autophagy represents a good target for PD therapeutics Sala et al. HD is a neurodegenerative disorder that is characterized by the loss of motor control and cognitive dysfunction. HD is caused by damages to the subcortical part of the forebrain, the striatum, which plays a key role in body movements.
HD is an autosomal dominant disease caused by the expansion of a CAG cytosine-adenine-guanine triplet repeat in exon 1 of the gene encoding huntingtin HTT protein. The polyglutamine polyQ tract in the mutant HTT protein encoded from the CAG repeat is responsible for the formation of toxic oligomers and aggregates.
Whether these aggregates are toxic remain to be elucidated Martin et al. The expansion of the HTT polyQ tract is 6—34 in normal individuals and 36— in affected individuals. The longer the length of tandem repeats in mutant HTT is, the easier it is to form aggregates and the earlier is the age of HD onset Juenemann et al. On the other hand, wild-type HTT function is not yet well-elucidated, but is essential for embryonic development Duyao et al.
Therefore, HD therapeutic approach should consider the importance of selectivity without interfering with wild-type HTT. Mutant HTT forms perinuclear cytoplasmic aggregates and intracellular inclusions, which can be removed by autophagy.
Previous studies have shown that autophagy induces the degradation of both aggregated and soluble forms of HTT and decreases toxicity in cell, fly, and mouse models of HD Ravikumar et al. Moreover, autophagy alteration has been observed in various types of HD models such as primary striatal neurons from HD mice or lymphoblasts of patients with HD Nagata et al. In general, inefficient macroautophagy is known to contribute to HD pathogenesis. More specifically, the ability of AVs to recognize cytosolic cargos is largely defective in HD cells. The autophagosome-lysosome pathway is normal or even increased in HD cells, but AVs fail to efficiently recognize and trap cytosolic cargos due to the interaction between mutant HTT and p62 Martinez-Vicente et al.
While CMA activity increases in response to macroautophagy dysfunction in the early stages of HD, this compensatory CMA activity continuously decreases with aging, leading to the onset of pathological symptoms Koga et al. This notion is also in line with the observation that HSP70 and its co-chaperone, HSP40, modulates polyQ aggregation by partitioning monomeric conformations Wacker et al.
HD pathogenesis is strongly influenced by neuronal autophagy dysfunction. However the molecular events, leading to autophagy dysfunction, remain elusive. Many therapeutic approaches to treat HD are under development to manipulate autophagy. Several reports suggest that autophagy activation alleviates behavioral motor abnormalities and neuropathology in HD model systems Cortes and La Spada, Trehalose, a disaccharide present in many non-mammalian species, induces macroautophagy in an mTOR-independent manner and ameliorates polyQ-mediated pathology in a HD mouse model Tanaka et al.
Similarly, rilmenidine, an imidazoline-1 receptor agonist, induces mTOR-independent autophagy and reduces the pathologic signs of the disease in a HD mouse model Rose et al. In a HD neuron model, N 10 -substituted phenoxazine is neuroprotective and decreases the accumulation of aggregated mutant HTT Tsvetkov et al.
HDAC6 was previously shown to be an essential link between autophagy activation and the UPS impairment to reduce neurodegeneration Pandey et al. The progressive degeneration of motor neurons in ALS eventually leads to death due to respiratory failure. Many factors such as oxidative stress, mitochondrial dysfunction, abnormalities of the immune system, and glutamate toxicity are known to cause sporadic ALS Kiernan et al.
In patients with sporadic ALS, the autophagy features were observed under electron microscopy in the cytoplasm of normal motor neurons and more frequently in degenerated motor neurons Sasaki, A dramatic decrease in mutant SOD1 toxicity was also observed in X-box-binding protein-1 XBP-1 , a key molecule in unfolded protein response, deficient mice, correlating with the increased levels of autophagy and the reduced accumulation of mutant SOD1 aggregates in the spinal cord Hetz et al.
In this study, Alfy overexpression decreases the expression of mutant proteins through autophagy and reduces mutant protein toxicity Han et al. Additionally, functions of several ALS-related genes were reported to be associated with autophagy. TDP43 turnover is known to be enhanced by autophagy activation and that autophagy-activating compounds improve TDP43 clearance and enhance survival in neuronal ALS models Barmada et al. Unlike other neurodegenerative disorders, the identification of autophagy-regulating drugs as potential ALS therapeutic agents is not much studied.
Therefore, several autophagic enhancers such as rapamycin, lithium, and trehalose are expected to function as pathology reliever in ALS. In general, rapamycin plays a neuroprotective role in several neurodegenerations. However, in ALS models, it showed beneficial and detrimental effects in various studies. In contrast, rapamycin moderately increases the survival of ALS mice deficient of mature lymphocytes.
Staats et al. Lithium also shows both protective and detrimental effects in ALS models. Lithium delay disease progression in patients with ALS. While this aspect needs to be further characterized using animal genetic models, combination strategies or modified autophagy enhancers may still be appropriate as ALS therapeutic approaches. Accumulated evidence revealed that neuronal autophagy is essential for the healthy aging of neurons. Moreover, neuronal autophagy is the major process for the degradation of an abnormal protein aggregate, which is the major cause of most neurodegenerative diseases such as AD, PD, HD, and ALS.
Increasing research in autophagy revealed several links connecting autophagy and neurodegenerative diseases. However, direct links and molecular mechanisms remain elusive and need to be further addressed. Nevertheless, the recent attempts to treat the autophagic impairment in neurodegeneration have focused on the induction of initial autophagy.
Therefore, it is critical to overcome lysosomal dysfunction when developing therapeutic strategies against neurodegenerative diseases. Research on autophagy as a potential therapeutic target for neurodegenerative disease treatment is only starting. Some compounds for the treatment of AD have been tested in human clinical trials. Other compounds for the treatment of the other neurodegenerative diseases are now in the preclinical phase. Despite research limitations, therapeutic approaches targeting autophagy are highly expected to contribute to the treatment of neurodegenerative diseases.
National Center for Biotechnology Information , U. Journal List Mol Cells v. Mol Cells. Published online Apr Author information Article notes Copyright and License information Disclaimer. Received Feb 6; Accepted Feb 9. All rights reserved. This article has been cited by other articles in PMC. Abstract Autophagy is a lysosome-dependent intracellular degradation process that allows recycling of cytoplasmic constituents into bioenergetic and biosynthetic materials for maintenance of homeostasis.
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Future studies may focus on identifying specific molecules that modulate each step in the autophagy pathway. Simeonidou C was responsible for conception and design of the manuscript, data collection, writing the manuscript, and critical supervision. We then interrogated different components of the PI 3 P regulatory machinery and found that ataxin-3 knockdown regulated Beclin levels. Selective transport of glucose, amino acids, and hormones across the blood-brain-barrier ensures ample supply of metabolites and local populations of glia cells release trophic factors under normal or energy restricted conditions. This article is published under license to BioMed Central Ltd.
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