source url 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.
Open in a separate window. Table 1. Autophagy-enhancing compounds that therapeutically targets neurodegenerative diseases. Ubiquitination and phosphorylation of Beclin 1 and its binding partners: Tuning class III phosphatidylinositol 3-kinase activity and tumor suppression. FEBS Lett. Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study.
LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Emerging regulation and functions of autophagy.
Cell Biol. Molecular interplay between mammalian target of rapamycin mTOR , amyloid-beta, and Tau: effects on cognitive impairments. Autophagy in neuroprotection and neurodegeneration: A question of balance. Future Neurol. Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Drug Discov.
Parkinsons Dis. The small heat shock protein B8 HspB8 promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis ALS Hum. Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. A caspase cleaved form of tau is preferentially degraded through the autophagy pathway. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.
Drugs Aging. Lithium delays progression of amyotrophic lateral sclerosis. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease.
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.
Role of autophagy in metabolic syndrome-associated heart disease. Autophagy and Aging. Cell 5 : Autophagy in mammalian development and differentiation. Nat Cell Biol 12 9 : Autophagy: Renovation of Cells and Tissues. Cell 4 : J Biol Chem 18 : Mol Biol Cell 20 7 : Cell 2 : Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7 7 : Nat Cell Biol 13 2 : Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature : Mol Cell 55 2 : The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function.
Autophagy 1 1 : ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase. Nat Cell Biol 15 7 : Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res 27 11 : Autophagy and cell reprogramming. Cell Mol Life Sci 72 9 : Annu Rev Biochem 85 1 : J Biol Chem 33 : J Cell Biol 4 : Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.
Science : Nat Immunol 10 11 : U Mol Cell 33 4 : The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.
Mol Cell 38 2 : Dev Cell 30 4 : Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 20 : Accumulation of autophagic vacuoles and cardiomyopathy in LAMPdeficient mice. Mol Cell 63 5 : Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration.
J Cell Biol 6 : Mol Biol Cell 25 8 : The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin Mol Cell 57 1 : Cell 6 : J Bacteriol 20 : Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1 2 : J Biol Chem 3 : Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy.
J Neurosci 31 21 : Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain Pathol 28 1 : The role of autophagy in neurodegenerative disease. Nat Med 19 8 Loss of autophagy in the central nervous system causes neurodegeneration in mice. Mol Cells 38 5 : Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy.
Hum Mol Genet 11 9 : Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci Alzheimer's disease genes and autophagy. Brain Res Autophagy protects neuron from Abeta-induced cytotoxicity.
Autophagy 5 4 : JAD 21 2 : Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64 2 : Cell Rep 5 1 : J Neurosci 28 27 : Neurodegenerative Tauopathies. Annu Rev Neurosci 24 1 : In vivo axonal transport deficits in a mouse model of fronto-temporal dementia. Neuroimage Clin 4: Hum Mol Genet 24 13 : J Biol Chem 17 : Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 15 3 : Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing.
Hum Mol Genet 18 21 : Neurobiol Dis 39 3 : Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain 7 : J Neuropathol Exp Neurol 74 4 : Brain 10 : J Cell Biol 1 : Cell 7 : Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits.
Brain 12 : Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer's disease neurons. J Clin Invest 6 : Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol 58 6 : Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer's disease brain. Neurobiol Dis 43 1 : Autophagy 12 10 : Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP Nat Commun 5: Nat Genet 41 10 : Arch Neurol 67 12 : Acta Neuropathol 6 : Neurobiol Dis Autophagy 13 12 : Cell Physiol Biochem 43 6 : Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease.
PloS one 5 4 : ee J Neurosci 33 32 : J Biol Chem 12 : Nano Lett 14 9 : Induction of autophagy by a novel small molecule improves abeta pathology and ameliorates cognitive deficits. PLoS One 8 6 : e Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry 18 8 : Mol Cell Biol 32 21 : J Biol Chem 2 : Pharmacol Res Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance.
J Mol Med 92 4 : Neuropharmacology Exp Gerontol Dendrobium nobile Lindl alkaloid, a novel autophagy inducer, protects against axonal degeneration induced by Abeta in hippocampus neurons in vitro. CNS Neurosci Ther 23 4 : Parkinson's Disease. Neuron 39 6 : Autophagy, its mechanisms and regulation: Implications in neurodegenerative diseases.
Ageing Res Rev Pathogenic Lysosomal Depletion in Parkinson's Disease.
J Neurosci 30 37 : Parkinson's Disease: Mechanisms and Models. Ann Neurol 73 2 : Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 27 : TFEB links autophagy to lysosomal biogenesis. J Neurosci 34 2 : J Neurochem 3 : Mutations in LRRK2 potentiate age-related impairment of autophagic flux. Mol Neurodegener LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages.
EMBO J 37 12 : e Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. PINK1 and Parkin — mitochondrial interplay between phosphorylation and ubiquitylation in Parkinson's disease. Febs J 2 : J Neurochem 2 : Mitochondrial Dysfunction and Oxidative Damage in parkin-deficient Mice. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress.
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 5 : PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2 : Ubiquitin is phosphorylated by PINK1 to activate parkin.
Nature PLoS Biol 8 1 : e The antioxidant Trolox helps recovery from the familial Parkinson's disease-specific mitochondrial deficits caused by PINK1- and DJdeficiency in dopaminergic neuronal cells. Mitochondrion 11 5 : Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson's disease. Mol Neurobiol 55 6 : Defects in trafficking bridge Parkinson's disease pathology and genetics.
Brain 3 : ATP13A2 variants in early-onset Parkinson's disease patients and controls.
Mov Disord 24 14 :