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Glia-specific autophagy dysfunction in ALS.

Semin Cell Dev Biol. 2019 May 28. pii: S1084-9521(19)30020-5. doi: 10.1016/j.semcdb.2019.05.024. [Epub ahead of print]

Authors/Editors: Strohm L, Behrends C.
Publication Date: 2019

Abstract

Neuronal cell death is the main pathological feature of chronic neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As age is strongly linked to NDs, these diseases are one of the leading medical and societal challenges faced by the rapidly aging western societies. Despite the increasing prevalence, the causes and mechanisms behind most NDs are still vague. A common hallmark of several NDs is the accumulation and aggregation of proteins. Prominent examples are amyloid beta and tau in Alzheimer's disease, α-synuclein in Parkinson's disease and transactive response DNA binding protein 43 kDa (TDP-43) in ALS and FTD. Under physiological conditions, protein quality control systems, namely the ubiquitin proteasome system and the autophagy machinery, eliminate such aberrant protein forms and thereby prevent proteotoxic stress. However, as proteins must unfold to undergo proteasomal degradation, aggregated proteins are poor substrates for the proteasome. Such proteins are thought to be primarily turned over by autophagy. Therefore, autophagy is considered a critical ND-protective pathway, which opens up potential new therapeutic interventions. One drawback is that the majority of research in NDs has been focused on elucidating the underlying pathomechanisms in neurons. However, neurons make up only about half of the brain cells with neuroglia being the other major central nervous system (CNS) cell type. Due to the ubiquitous presence of disease-causing mutations in all cells of the CNS, it is likely that non-neuronal cells contribute to the disease onset and/or progression. While our understanding of the roles of autophagy and its contribution to neurodegeneration in neurons deepened considerably over the last years, still comparatively little is known about the functions and disease contribution of the autophagy machinery in glia cells.

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