Abstract
Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.
Highlights
Neurodegenerative DiseasesNeurodegenerative diseases (NDDs) are a heterogeneous group of neurological disorders, characterized by a progressive loss of particular subsets of neurons in different functional anatomic systems of the brain or the spinal cord [1]
Considering Amyotrophic Lateral Sclerosis (ALS), we have previously described the implication of oxidative stress (OS), neuroinflammation, and proteostasis in this disease
Considering the physiopathology of these diseases, there are a plethora of common pathological mechanisms involved in onset and development, such as the apparition of aberrant protein aggregates, oxidative damage, metal ions dyshomeostasis, abnormal neuroinflammatory response, and extensive neuronal death
Summary
Neurodegenerative diseases (NDDs) are a heterogeneous group of neurological disorders, characterized by a progressive loss of particular subsets of neurons in different functional anatomic systems of the brain or the spinal cord [1]. Tremendous efforts have been made to find effective disease-modifying treatments for these devastating diseases; the lack of efficient diagnosis and the still unknown causes of NDDs have hampered the development of successful therapies. NDDs pathophysiology represents a complex network of pathological events where several factors participate in their onset and development. Increasing evidence demonstrates that NDDs share many common pathophysiological mechanisms [2,3,4]. Numerous genetic mutations are associated with the onset of NDDs [5]; these “familial forms” represent less than 5% of the cases, and the vast majority of the cases are sporadic. OS has been widely recognized as an important factor in the etiology of NDDs [7,8], yet its role as a cause or consequence is debated. Therapeutic strategies based on these common pathological mechanisms will be discussed
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