Autophagy gone awry in neurodegenerative diseases

Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.
Nature Neuroscience (Impact Factor: 16.1). 07/2010; 13(7):805-11. DOI: 10.1038/nn.2575
Source: PubMed

ABSTRACT Autophagy is essential for neuronal homeostasis, and its dysfunction has been directly linked to a growing number of neurodegenerative disorders. The reasons behind autophagic failure in degenerating neurons can be very diverse because of the different steps required for autophagy and the characterization of the molecular players involved in each of them. Understanding the step(s) affected in the autophagic process in each disorder could explain differences in the course of these pathologies and will be essential to developing targeted therapeutic approaches for each disease based on modulation of autophagy. Here we present examples of different types of autophagic dysfunction described in common neurodegenerative disorders and discuss the prospect of exploring some of the recently identified autophagic variants and the interactions among autophagic and non-autophagic proteolytic systems as possible future therapeutic targets.

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Available from: Esther Wong, Jun 24, 2014
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    • "The autophagic process encompasses several sequential steps—initiation and nucleation of the autophagic vesicles (AVs), elongation and closure of the autophagosome membrane, docking of the autophagosome with the lysosome, and degradation of the cytoplasmic material inside the autolysosome—that are controlled by a set of products of autophagy-related genes (Atg) (He and Klionsky, 2009; Nakatogawa et al., 2009). Proper autophagic flux involves the execution of autophagosome formation and clearance by lysosomes (Wong and Cuervo, 2010). A defective autophagic–lysosomal pathway has been posited as a contributing factor in several neurodegenerative diseases, including Alzheimer's disease (AD). "
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    ABSTRACT: Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.
    DNA and Cell Biology 02/2015; 34(4). DOI:10.1089/dna.2014.2757 · 2.06 Impact Factor
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    • "In addition, marked elevations in the level of oxidatively damaged, phosphorylated and nitrated proteins have been observed in dopaminergic neurons of the SNpc in PD (Alam et al. 1997; Giasson et al. 2000; Fujiwara et al. 2002). This implicates that the failure of either or both the ubiquitin– proteasome system (UPS) (Olanow and McNaught 2006; Cook and Petrucelli 2009) and the autophagic–lysosomal system (Martinez-Vicente and Cuervo 2007; Wong and Cuervo 2010) results in a decreased ability for clearing damaged and/or misfolded proteins in PD. Use of Lactacystin, an irreversible UPS inhibitor, has received increased research attention since it can induce Parkinsonism in rodents. "
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    ABSTRACT: A rostral brainstem structure, the pedunculopontine nucleus (PPN), is severely affected by Parkinson's disease (PD) pathology and is regarded a promising target for therapeutic deep-brain stimulation (DBS). However, understanding the PPN's role in PD and assessing the potential of DBS are hampered by the lack of a suitable model of PPN degeneration. Rats were rendered Parkinsonian through a unilateral substantia nigra pars compacta (SNpc) stereotaxic injection of the proteasome inhibitor Lactacystin, to investigate whether the lesion's pathological effects spread to impact the integrity of PPN cholinergic neurons which are affected in PD. At 5 weeks post-surgery, stereological analysis revealed that the lesion caused a 48 % loss of dopaminergic SNpc neurons and a 61 % loss of PPN cholinergic neurons, accompanied by substantial somatic hypotrophy in the remaining cholinergic neurons. Magnetic resonance imaging revealed T2 signal hyper-/hypointensity in the PPN of the injected hemisphere, respectively at weeks 3 and 5 post-lesion. Moreover, isolated PPN cholinergic neurons revealed no significant alterations in key autophagy mRNA levels, suggesting that autophagy-related mechanisms fail to protect the PPN against Lactacystin-induced cellular changes. Hence, the current results suggest that the Lactacystin PD model offers a suitable model for investigating the role of the PPN in PD.
    Brain Structure and Function 01/2015; 220(1):479-500. DOI:10.1007/s00429-013-0669-5 · 5.62 Impact Factor
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    • "Defects in autophagosome formation and loss of basal autophagy may be implicated as a cause of neurodegeneration (Hara et al., 2006, Wong and Cuervo, 2010), while an increased autophagic activity may help to clear key aggregated proteins involved in neurodegenerative pathologies, such as mutant α-synuclein and huntingtin proteins which contribute to Parkinson and Huntington diseases, respectively (Engelender, 2008; Sarkar et al., 2007). There is also mounting evidence that if the autophagosome-lysosomal degradation is impaired, this could disturb the processing of APP and participate to the development of AD pathology. "
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    ABSTRACT: In neurogenerative diseases, comprising Alzheimer's (AD), functional alteration in autophagy is considered one of the pathological hallmarks and a promising therapeutic target. Epidemiological investigations on the possible causes undergoing these diseases have suggested that electromagnetic fields (EMF) exposition can contribute to their etiology. On the other hand, EMF have therapeutic implications in reactivating neuronal functionality. To partly clarify this dualism, the effect of low-frequency EMF (LF-EMF) on the modulation of autophagy was investigated in human neuroblastoma SH-SY5Y cells, which were also subsequently exposed to Aβ peptides, key players in AD. The results primarily point that LF-EMF induce a significant reduction of microRNA 30a (miR-30a) expression with a concomitant increase of Beclin1 transcript (BECN1) and its corresponding protein. Furthermore, LF-EMF counteract the induced miR-30a up-regulation in the same cells transfected with miR-30a mimic precursor molecules and, on the other side, rescue Beclin1 expression after BECN1 siRNA treatment. The expression of autophagy-related markers (ATG7 and LC3B-II) as well as the dynamics of autophagosome formation were also visualized after LF-EMF exposition. Finally, different protocols of repeated LF-EMF treatments were assayed to contrast the effects of Aβ peptides in vitro administration. Overall, this research demonstrates, for the first time, that specific LF-EMF treatments can modulate in vitro the expression of a microRNA sequence, which in turn affects autophagy via Beclin1 expression. Taking into account the pivotal role of autophagy in the clearance of protein aggregates within the cells, our results indicate a potential cytoprotective effect exerted by LF-EMF in neurodegenerative diseases such as AD. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 11/2014; 229(11). DOI:10.1002/jcp.24631 · 3.84 Impact Factor
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