Article

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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    • "Most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Huntington's disease (HD), are associated with the misfolding and aggregation of specific proteins. An efficient protein quality control system is particularly crucial in postmitotic cells like neurons, where the accumulation of abnormal protein inclusions and oligomers cannot be diluted by cell division (Wong and Cuervo, 2010). Protein aggregation can alter essential cellular functions, leading to neurological impairment and in many cases neuronal death (Vance et al., 2009). "

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    • "One possible cellular response is autophagy. Several lines of evidence have suggested that autophagy activation alleviates mutant SOD1-linked toxic insults (Wong and Cuervo, 2010). SOD1G93A- transgenic mice show numerous microtubule-associated protein 1A/ 1B-light chain 3 (LC-3)-labeled autophagic vacuoles in the spinal motor neurons (Li et al., 2008). "
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    ABSTRACT: Proteotoxicity of misfolded, disease-causing proteins is deeply implicated in the pathomechanisms for neurodegenerative diseases including copper-zinc superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS). However, the precise cellular quality control (QC) mechanisms against aggregation of misfolded mutant SOD1 proteins remain elusive. Here, we found that the Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase, which catalyzes mono-ubiquitination to the substrate, was dysregulated in the cellular and mouse models of ALS and that it preferentially interacted with various mutant forms of SOD1. Intriguingly, the motor neurons of presymptomatic ALS mice have diminished MGRN1 cytoplasmic distribution. MGRN1 was partially recruited to mutant SOD1 inclusions where they were positive for p62 and Lamp2. Moreover, overexpression of MGRN1 reduced mutant SOD1 aggregation and alleviated its proteotoxic effects on cells. Taken together, our findings suggest that MGRN1 contributes to the clearance of toxic mutant SOD1 inclusions likely through autophagic pathway, and, most likely, the sequestration of MGRN1 sensitizes motor neurons to degeneration in the ALS mouse model. Furthermore, the present study identifies the MGRN1-mediated protein QC mechanism as a novel therapeutic target in neurodegenerative diseases.
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    • "Moreover, KA-induced excitotoxicity induces apoptotic neuronal death, which has been defined as a type II programmed cell death, viainduction of autophagic stress in the striatum [7]. Although it is still controversial whether autophagic stress leads to neuronal death [8], accumulating evidences support that abnormal overactivation of autophagy according to the type and degree of environmental changes or stress stimuli may induce neurodegeneration involved in brain diseases [7, 9–11]. Therefore, these reports suggest that the control of neuroinflammation and autophagic stress induced by excitotoxicity may be important to maintain normal hippocampal system and prevent the induction of epileptic seizures. "
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    ABSTRACT: Kainic acid (KA) is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS) in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3), and attenuated an increase in tumor necrosis factor-α (TNFα) in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo.
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