Our staff editors continue to share brilliant, thoughtful, and meaningful topics and articles in the recommended series.
This week, we would like to share several the latest articles on Autophagy related to neurodegenerative diseases.
Title: The role of inflammation in neurodegenerative diseases
Authors: Stanley H.Appel, David R.Beers, WeihuaZhao
Type: Book Chapter
The immune system plays early and important inflammatory roles in the pathophysiology of diverse neurodegenerative disorders. This inflammation is not restricted to the central nervous system (CNS) in neurodegenerative diseases, but is also expressed systemically. In fact, peripheral immune alterations and inflammation augment disease burden and rates of disease progression. Thus neurodegeneration is a multifactorial, multisystem syndrome in which the CNS and peripheral immune systems play important roles in development and progression of disease. Inflammation was previously considered the consequence and not the cause of neuronal injury. However, more recent evidence suggests that the immune system actively contributes to neuroprotection at early phases of disease and contributes to neurotoxicity in later phases of disease. Neuronal injury is non-cell-autonomous and depends on well-orchestrated dialogues between peripheral and CNS immune systems, glia, and neurons. This chapter will review the proposed mechanisms of inflammation in the context of neuronal protection and injury based on animal models and human disease. The cumulative evidence suggests that inflammation plays a central role in pathology, and manipulating microglial and lymphocytic functions has the potential to ameliorate devastating neurodegenerative disorders.
Access this article: https://doi.org/10.1016/B978-0-323-85654-6.00036-8
Title: Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons
Authors: Jason P. Chua, Karan Bedi, Michelle T. Paulsen, Mats Ljungman, Elizabeth M.H. Tank, Erin S. Kim, Jonathon P. McBride, Jennifer M. Colón-Mercado, Michael E. Ward, Lois S. Weisman, Sami J. Barmada
●Neurons are uniquely resistant to methods of inducing autophagy
●iPSC-derived rat and human neurons highly express the autophagy suppressor MTMR5
●MTMR5 is necessary and sufficient to inhibit autophagosome biogenesis
●Knockdown of MTMR5 enhances autophagic degradation of TDP-43
Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs), and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not the unrelated phosphatase MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Our findings thus establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell-type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.
Access this article: https://doi.org/10.1016/j.cub.2022.04.053
Title: Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications
Authors: Ling Zou, Minru Liao, Yongqi Zhen, Shiou Zhu, Xiya Chen, Jin Zhang, Yue Hao, Bo Liu
UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.
Access this article: https://doi.org/10.1016/j.apsb.2022.06.004
Title: Molecular interaction of stress granules with Tau and autophagy in Alzheimer's disease
Authors: Qin-YuanYu, Ling-Qi Ye, Hong-Lei Li
●The abnormal regulation of stress granule formation and clearance promotes the pathological process of AD.
●The aggregation of stress granules and RNA-binding proteins facilitate the misfolding and propagation of Tau protein.
●Autophagy-lysosome system dysfunction in Alzheimer's Disease inhibits SG removal.
Stress Granules (SGs) are RNA granules composed of untranslated mRNA and associated proteins, which are related to the cytoplasmic metabolism of mRNA in response to cellular stress and certain drug stimuli. Physiological SGs are dynamic structures that protect cells from the effects of stress, and continuous stress ripens the SGs into more stable complexes. Numerous studies have found that dysregulation of RNA metabolism in stress response led to misfolded protein aggregation in the pathophysiology of neurodegenerative diseases. For example, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD), SGs aggregation is mainly due to up-regulation of SGs formation and down-regulation of SGs clearance. Recent studies have revealed the role of SGs in the pathogenesis and pathology of AD, especially the interaction of SGs and RNA-binding proteins with Tau and autophagy. Aggregation of SGs and increased RNA-binding proteins, especially TIA1, can facilitate Tau misfolding and propagation, and vice versa. Autophagy dysfunction disrupts the normal pathway of SGs clearance. In this review, we summarized the regulation of SGs and their relationship with Tau protein and autophagy, as well as the pathological mechanisms of AD such as RNA splicing, microglial cell proliferation and phagocytosis.
Access this article: https://doi.org/10.1016/j.neuint.2022.105342
Title: Organization of the autophagy pathway in neurons
Authors: David K. Sidibe, Maria C. Vogel, Sandra Maday
●Autophagy is a highly compartmentalized pathway critical for neuroprotection.
●Axonal autophagosomes form distally and travel retrogradely toward the soma.
●Dendritic autophagic vacuoles travel bidirectionally and arrest at synapses with activity.
●Autophagy regulates the synaptic proteome to modulate neurotransmission.
●Defects in steps of the autophagy pathway are associated with neurodegeneration.
Macroautophagy (hereafter referred to as autophagy) is an essential quality-control pathway in neurons, which face unique functional and morphological challenges in maintaining the integrity of organelles and the proteome. To overcome these challenges, neurons have developed compartment-specific pathways for autophagy. In this review, we discuss the organization of the autophagy pathway, from autophagosome biogenesis, trafficking, to clearance, in the neuron. We dissect the compartment-specific mechanisms and functions of autophagy in axons, dendrites, and the soma. Furthermore, we highlight examples of how steps along the autophagy pathway are impaired in the context of aging and neurodegenerative disease, which underscore the critical importance of autophagy in maintaining neuronal function and survival.
Access this article: https://doi.org/10.1016/j.conb.2022.102554