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Autophagy in the Central Nervous System: Implications for Neurodegenerative Disorders

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The autophagy-lysosomal pathway is a major proteolytic pathway that in mammalian systems mainly comprises of macroautophagy and chaperone-mediated autophagy. The former is relatively non-selective and involves bulk degradation of proteins and organelles, whereas the latter is selective for certain cytosolic proteins. These autophagy pathways are important in development, differentiation, cellular remodeling and survival during nutrient starvation. Autophagy is crucial for neuronal homeostasis and acts as a local housekeeping process, since neurons are post-mitotic cells and require effective protein degradation to prevent accumulation of toxic aggregates. A growing body of evidence now suggests that dysfunction of autophagy causes accumulation of abnormal proteins and/or damaged organelles. Such accumulation has been linked to synaptic dysfunction, cellular stress and neuronal death. Abnormal autophagy may be involved in the pathology of both chronic nervous system disorders, such as proteinopathies (Alzheimer's, Parkinson's, Huntington's disease) and acute brain injuries. Although autophagy is generally beneficial, its aberrant activation may also exert a detrimental role in neurological diseases depending on the environment and the insult, leading to autophagic neuronal death. In this review we summarize the current knowledge regarding the role of autophagy-lysosomal pathway in the central nervous system and discuss the implication of autophagy dysregulation in human neurological diseases and animal models.

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Keywords: ASYN gene; Alzheimer's disease; Ambra1; Amyotrophic lateral sclerosis; Atg14L; Autophagosome; Bafilomycin; Batten disease; C elegans; CHMP4B; Creutzfeldt-Jakob disease; ER-phagy; ESCRT; Frontotemporal dementias; HDAC6; Huntington's disease; KFERQ; LAMP-2A; LAMP-2A receptor; LC3; Lewy body dementias; MAP1LC3; MEF2D; NIEMANN-PICK C DISEASE; Parkinson's disease; Prion Diseases; Rubicon; SMER; Scrg1; UVRAG; amphisomes; amyloidogenesis; autophagolysosomes; autophagy-lysosomal pathway; chaperone-mediated autophagy; dentatorubral; mTOR; macroautophagy; metamphetamine-induced injury; microautophagy; neurodegenerative diseases; neuronal ceroid lipofuscinosis; pallidoluysian atrophy; pexophagy; polyQ diseseases; rapamycin; reticulophagy; spinobulbar muscular atrophy; temsirolimus

Document Type: Research Article

Publication date: 01 December 2010

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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