Abstract
Autophagy is an important cellular self-digestion and recycling pathway that helps in maintaining cellular homeostasis. Dysregulation at various steps of the autophagic and endolysosomal pathway has been reported in several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington disease (HD) and is cited as a critically important feature for central nervous system (CNS) proteostasis. Recently, another molecular target, namely transcription factor EB (TFEB) has been explored globally to treat neurodegenerative disorders. This TFEB, is a key regulator of autophagy and lysosomal biogenesis pathway. Multiple research studies suggested therapeutic potential by targeting TFEB to treat human diseases involving autophagy-lysosomal dysfunction, especially neurodegenerative disorders. A common observation involving all neurodegenerative disorders is their poor efficacy in clearing and recycle toxic aggregated proteins and damaged cellular organelles due to impairment in the autophagy pathway. This dysfunction in autophagy characterized by the accumulation of toxic protein aggregates leads to a progressive loss in structural integrity/functionality of neurons and may even result in neuronal death. In recent years TFEB, a key regulator of autophagy and lysosomal biogenesis, has received considerable attention. It has emerged as a potential therapeutic target in numerous neurodegenerative disorders like AD and PD. In various neurobiology studies involving animal models, TFEB has been found to ameliorate neurotoxicity and rescue neurodegeneration. Since TFEB is a master transcriptional regulator of autophagy and lysosomal biogenesis pathway and plays a crucial role in defining autophagy activation. Studies have been done to understand the mechanisms for TFEB dysfunction, which may yield insights into how TFEB might be targeted and used for the therapeutic strategy to develop a treatment process with extensive application to neurodegenerative disorders. In this review, we explore the role of different transcription factor-based targeted therapy by some natural compounds for AD and PD with special emphasis on TFEB.
Highlights
Factors Modulating Alzheimer’s DiseaseNeurodegenerative diseases are a multifactorial heterogeneous group of nervous system disorders characterized by structural/functional dysfunction of neurons in the brain (Sheikh et al, 2013)
The findings in this study reveal that Resveratrol; which activates sirtuin 1 (SIRT1); which in turn deacetylates Transcription factor EB (TFEB), could regulate lysosomal biogenesis and fAβ degradation making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in Alzheimer’s disease (AD)
MiRNA are involved in the TFEB mediated regulation of AD and Parkinson’s disease (PD)
Summary
Neurodegenerative diseases are a multifactorial heterogeneous group of nervous system disorders characterized by structural/functional dysfunction of neurons in the brain (Sheikh et al, 2013). Aβ accumulation starts from the temporal lobe region of the brain and later gets diffused to the entire cortex region during the final stages of the disease This deposition and accumulation of amyloid plaques result in synaptic dysfunctions, inflammatory responses, and neuronal dysfunction that causes neurodegeneration, a major characteristic of AD and correlates with clinical symptoms (DeTure and Dickson, 2019). Transcription factor EB (TFEB) is an important agent that plays a vital role in redox-dependent and autophagy regulation and is activated by several different stimuli such as cytokines, lipopolysaccharide (LPS), and oxidative stress during inflammatory events in neurodegeneration (Brady et al, 2018) Since these transcription factors and mutations inside them have been discovered to be the root cause of many diseases and their involvement has been found in many neurological disorders, they have become potential therapeutic targets for the development of effective drugs and medicines. Disruption of Keap1-Nrf interaction or alterations of Nrf activity can increase the endogenous antioxidant/detoxifying systems of the brain, maintaining a redox balance and providing protection against oxidative stress in various neurodegenerative disorders (Tu et al, 2019)
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