Autophagy impairment: a crossroad between neurodegeneration and tauopathies
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Autophagy impairment: a crossroad between neurodegeneration and tauopathies Melissa Nassif1,2 and Claudio Hetz1,2,3,4* See research article: http://www.molecularneurodegeneration.com/content/7/1/48
Abstract Most neurodegenerative diseases involve the accumulation of misfolded proteins in the nervous system. Impairment of protein degradation pathways such as autophagy is emerging as a consistent and transversal pathological phenomenon in neurodegenerative diseases, including Alzheimer´s, Huntington´s, and Parkinson´s disease. Genetic inactivation of autophagy in mice has demonstrated a key role of the pathway in maintaining protein homeostasis in the brain, triggering massive neuronal loss and the accumulation of abnormal protein inclusions. However, the mechanism underlying neurodegeneration due to autophagy impairment remains elusive. A paper in Molecular Neurodegeneration from Abeliovich´s group now suggests a role for phosphorylation of Tau and the activation of glycogen synthase kinase 3β (GSK3β) in driving neurodegeneration in autophagy-deficient neurons. We discuss the implications of this study for understanding the factors driving neurofibrillary tangle formation in Alzheimer´s disease and tauopathies.
The progressive accumulation of misfolded proteins in the brain is implicated in a vast group of human diseases, including the most prevalent neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, and amyotrophic lateral sclerosis. These diseases are classified as protein misfolding disorders (PMDs) [1]. Despite representing an extensive and active field of research, in most cases the factors driving protein misfolding and neurodegeneration in the most common *Correspondence: [email protected]; [email protected] 1 Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile 4 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA Full list of author information is available at the end of the article
sporadic PMD cases remain poorly understood. Alteration in protein homeostasis networks is emerging as a factor driving neuronal dysfunction, where disruption in protein quality control mechanisms and protein clearance pathways may contribute to the accumulation of abnormally folded proteins in the brain. The macroautophagy pathway (here referred to as autophagy) is the main degradation route for long-lived proteins, damaged organelles, and protein aggregates. Autophagy is a highly regulated process, characterized by the formation of double- or multi-membrane vesicles (autophagosomes) that sequester portions of cytosol, which are then delivered for degradation following fusion with lysosomes (Figure 1a). Stimulation of autophagy results in the degradation of most aggregate-prone mutant proteins genetically linked to PMDs [2]. In addition, the accumulation of most of these mutant proteins upregulates autophagy activity through poorly defined mechanisms, and operates a
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