Neurodegenerative diseases are a class of neurological disorders, which critically harm the lives of millions of people worldwide. They are characterized by progressive loss of neurons in the nervous system. The collapse of the neural networks associated with loss of neurons, which are unable to effectively renew because of their terminally differentiated post-mitotic nature, result in the failure of the core communicative connections, leading to impaired memory, cognition, behavior, sensory, and/or motoric performance. Neurodegenerative diseases are complex disorders in which multiple factors such as genomic, epigenomic, cerebrovascular, metabolic, environmental, and others, converge to outline a progressive neurodegenerative phenotype. Concomitant with the rise in longevity over the past decades, there has been an escalation in the incidence of neurodegenerative disorders. Although neurodegenerative diseases are characteristically defined by particular protein accumulations and anatomic vulnerability, they share multiple fundamental processes associated with the progressive neuronal dysfunction and death, such as proteotoxic stress and its associated dysfunctions in ubiquitin-proteasome and autophagosome/lysosome systems, oxidative stress, programmed cell death, and neuroinflammation. It has been agreed that neurodegenerative diseases are defined by a set of common attributes including: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy metabolism, DNA and RNA defects, inflammation, and neuronal cell death (Figure ). Distinctive protein aggregation is a key pathological hallmark of a variety of neurodegenerative diseases and is related to virtually all other neurodegeneration attributes. It often serves for diagnosis and disease classification. In neurodegenerative diseases, symptoms generally reflect the disruption of specific neuronal networks, and synaptic failure is an early event preceding neuronal loss, since neuronal network function requires precise synaptic function. The accumulation of ubiquitinated, aggregated proteins in many neurodegenerative diseases indicates altered, abnormal proteostasis. Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases and represent another hallmark of neurodegeneration related to all other degeneration attributes. Mitochondrial dysfunction is repetitively involved in the pathogenesis of diverse neurodegenerative diseases. It is associated with certain molecular and cellular defects, whose impact at different levels of multifactorial nature including the calcium and iron homeostasis, energetic balance and/or oxidative stress. Figure . Hallmarks of neurodegenerative diseases and relationships between them