Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

(2021) 28:70 Chang et al. J Biomed Sci https://doi.org/10.1186/s12929-021-00766-y Open Access REVIEW Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases Ching‑Pang Chang1,2, Kuo‑Chen Wu2,3, Chien‑Yu Lin1,2 and Yijuang Chern1,2* Abstract In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progres‑ sively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past 2A adenosine receptors) have been actively investigated as two decades, adenosine receptors (particularly A1 and A important drug targets in major degenerative diseases. Unfortunately, except for an A 2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson’s disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis. Keywords: Adenosine, ATP, ENTs, Mitochondria, Therapeutic treatment, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Neuroinflammation Background Adenosine is a purine nucleoside. It serves as a neurotransmitter and neuromodulator in the central nervous system (CNS). In addition, adenosine is an essential component of energy production and is utilized in all living cells. Adenosine can be produced during the *Correspondence: 1 Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan Full list of author information is available at the end of the article catabolism of adenosine triphosphate (ATP), which is catalyzed by ectonucleotidases and endonucleotidases [145]. Extracellular and intracellular adenosine levels are modulated through equilibrative nucleoside transporters (ENTs) that bidirectionally transport adenosine across the plasma membrane down a concentration gradient and concentrative nucleoside transporters (CNTs) that transport adenosine into cells in a N a+-dependent manner against the concentration gradient [193]. Extracellular and intracellular adenosine play distinct roles © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chang et al. J Biomed Sci (2021) 28:70 in modulating various physiological functions (e.g., immune responses, blood–brain barrier (BBB) permeability, neuronal activity, and energy balance) in the CNS. Extracellular adenosine regulates intercellular signaling via adenosine receptors (A1R, A2AR, A2BR, and A3R) on the cell surface. In contrast, intracellular adenosine is important in the regulation of energy metabolism and DNA methylation [9, 35, 37, 48, 71, 198]. Disruption of adenosine homeostasis in the brain has been implicated in various pathophysiological dysfunctions, such as sleep disorders, cognitive impairment, and neuroinflammation [63, 198]. In the present review, we summarize the emerging role of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases and possible new treatment developments based on these findings. Most degenerative diseases are associated with abnormal aggregation of a disease-causing protein [203]. Specifically, the major pathogenic hallmarks of Alzheimer’s disease (AD) are the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular tau tangles [32]. Brains of patients with Parkinson’s disease (PD) commonly contain Lewy bodies with misfolded α-synuclein [28]. Huntington’s disease (HD) is caused by the formation of intracellular inclusions of mutant Huntingtin (mHTT), which contains an abnormal expansion of CAG repeats [169]. Amyotrophic lateral sclerosis (ALS) shows progressive loss of motor neurons with the accumulation of ubiquitinated TAR DNA-binding protein-43 (TDP43) [166]. Although these degenerative diseases present with distinct clinical symptoms and affect different brain areas, poor energy homeostasis and mitochondrial dysfunction have been commonly documented [34, 57, 88, 129, 195, 233]. Furthermore, accumulating evidence also implicates dysregulated purine metabolism and abnormal expression of adenosine metabolism enzymes in these neurodegenerative diseases [8, 25, 90, 99, 114, 127, 217, 230]. Together, these findings suggest a possible association between purine metabolism and mitochondrial function in protein misfolding diseases. Specific details are discussed in the following sections. Adenosine metabolism enzymes The level of intracellular and extracellular adenosine is tightly regulated by multiple enzymes, including ectonucleotidases, endonucleotidases, adenosine deaminase (...truncated)