Editorial [ Neurodegenerative Disorders: From Molecules to Man (Part 2) Guest Editors: Giuseppe Di Giovanni, Vincenzo Di Matteo and Ennio Esposito ]

Neurons are typically post-mitotic cells. This means that they are expected to have a life span comparable to that of their carriers. Unfortunately, sometimes, they die prematurely as a result of complex processes known as “neurodegeneration”. Neurodegenerative diseases are now generally considered a group of disorders that seriously and progressively impair the functions of the nervous system through causing the selective neuronal vulnerability of specific brain regions. Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer Disease (AD), Multiple Sclerosis (MS), and prion disease represent several distinct categories of disease and each manifests its own unique symptoms. However, the diseases share several common features, particularly the aggregation and deposition of abnormal proteins. Neurodegenerative disorders are associated with high morbidity, and few or no effective treatments have been available until now. Neurodegenerative diseases represent a threat to mankind in a variety of guises and induce chronic suffering and debilitation in about 2% of the worldwide population. Moreover, the increase in lifespan of western populations will mean that these neurodegenerative diseases will become more common. Consequently, it is estimated that the number of PD patients will double to between 8.7 and 9.3 million by 2030. As a group, these disorders are a major burden on health care systems compared with other causes of death and the costs of treatment are expected to rise sharply. Despite the enormous amount of progress we have made in terms of understanding the aetiologies of these diseases in the last few years, important questions remain unanswered. This special number deals with this hot topic and is produced by leading groups in the neuroscience field with the aim of summarizing recent advances in genetic, epideniological, molecular and cellular biology research that have increased our knowledge of the mechanisms that give rise to degenerative processes and, in general, to alterations of the structure and function of the nervous system. These contributions give insight into new pharmacological therapies for their treatment and review new and old drugs aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. The pharmaceutical industry faces arguably its most difficult challenge in attempting to develop therapeutics for neurodegenerative disease. The development of disease-modifying therapeutics that addresses the principal causes of neurodegenerative disease is still in its infancy. Moreira et al. review the role played by oxidative stress in the development and progression of AD and show how ROSmediated oxidative damages proteins, lipids, nucleic acids and sugars in AD and how this damage results from extensive mitochondrial and metal abnormalities. They present data supporting the notion that the oxidative modifications that occur in AD may elicit compensatory mechanisms, such as Aβ deposition and hyperphosphorylated tau that try to restore the redox balance in an attempt to avoid neuronal death. However, with the progression of AD and the consequent increase of reactive species, efficient removal of Aβ-metal complexes and hyperphosphorylated tau would be overtaken by their disproportionately high generation, resulting in an uncontrollable growth of plaques and NFTs and, consequently, an increase in reactive species generation. Amyotrophic lateral sclerosis (ALS) is the disorder reviewed by Tripathi and Al-Chalabi. This is a neurodegenerative disease of motor neurons resulting in progressive paralysis and respiratory failure. About 1 in 250,000 people suffer from ALS. The causes of ALS are largely unknown, but the only disease-modifying therapy, riluzole, was designed based on one hypothesis of disease causation, the excitotoxic hypothesis. In this paper they review the current situation regarding ALS and new therapeutic opportunities. The last two papers are about PD. Ali Qureshi et al. review the relation between vitamin B12 deficiency and neurotoxicity of homocysteine and nitrite (a metabolite of nitric oxide) in PD patients treated with levodopa (L-Dopa). A linear relationship between the CSF levels of nitrite with Glutamic acid and homocysteine exists and suggests that the production of nitrite is interrelated with the neurotoxic level of homocysteine. The levels of nitrite and homocysteine resulting in the deficiency of vitamin B12 are some of the factors promoting degeneration in PD through neurotoxic effects. Therefore, higher dietary intakes of folate, vitamin B12, and vitamin B6 might decrease the risk of PD through decreasing plasma homocysteine. Finally, Di Giovanni tries to answer the difficult question of the possibility of preventing PD in the future. Indeed, PD is still fatal, there is at present no cure for it and there are no proven therapies for prevention. Although there is evidence of the existence of risk and protective factors, these are not strong enough to warrant specific measures in an attempt to diminish risk or enhance protection. In the first part of his review new neuroprotective and neurorestorative therapies with their advantages and disadvantages are discussed. In the latter section, various dietary recommendations, lifestyle, environmental and other factors in reducing the risk of PD are analysed. The scenario that results from this special issue is that, despite the enormous research focused on neurodegenerative disorders, the underlying pathophysiology is not yet understood in sufficient detail. The situation is certainly a consequence of the complex interplay of genes, environment and their myriad interactions. There is not as yet a clear means of establishing efficacy in slowly progressing, late-onset disorders. Given the nature of these diseases, future therapeutics will need to be paired with tests for biomarkers indicating onset of brain pathology that precedes overt clinical symptoms. Therefore, it is of paramount importance to reveal those who are at high risk of developing these neurological disorders and allow them start an early program of prevention. This might involve a brain-healthy diet, very similar to a heart-healthy diet, and moderate physical activity with the aim of avoiding the other risk factors known so far.