Editorial [Hot topic: Central and Peripheral Metabolic Changes in Neurodegenerative Diseases (Guest Editor: Ana Cristina Rego)]

Over the past decades, metabolic dysfunction has emerged as one of the most common pathological condition underlying the neurodegenerative process in distinct disorders of the central and peripheral nervous system. Due to improvements in life expectancy, the world's population is ageing rapidly and the incidence of neurodegenerative diseases linked to protein misfolding and aggregation has increased and will dramatically increase over the next generations. Thus, understanding the basic mechanisms of neurodegeneration and identifying novel disease targets is urgently needed, so that new therapeutic strategies may be implemented. This review issue on ‘central and peripheral metabolic changes in neurodegenerative diseases’ revisits the fundamental concepts of bioenergetic deficits and covers the latest research-based developments on central and peripheral metabolic abnormalities in distinct neuron diseases. The theme of this review issue was inspired in the PENS Summer School on metabolic aspects of chronic brain diseases, which was held last year in Germany and involved some contributors of the present issue. Both the clinical and basic features of neurodegenerative diseases, including Alzheimer's disease, prion diseases, Huntington's disease (an autosomal dominant disease), Parkinson's disease, and motor neuron diseases, are described in this issue. Although some of these disorders have a pure genetic origin, the most common forms are sporadic, i.e., of unknown etiology. Interestingly, despite affecting selective areas in the brain, metabolic changes in peripheral cells or tissues and hypothalamic-neuroendocrine crosstalk have been also described, which may contribute for disease pathogenesis and/or constitute important biomarkers relevant for defining disease progression. Regarding the lower motor neuron diseases, which include spinal muscular atrophy, spinal bulbar muscular atrophy or Kennedy's disease (two purely genetic diseases) and amyotrophic lateral sclerosis, the muscle fibers and the neuromuscular junction have been also hypothesized as sites of crucial pathogenic events and therapeutic development. Importantly, distinct parallel pathological features may take place among the diverse group of neurodegenerative disorders, including protein aggregation, transcriptional deregulation and mitochondrial dysfunction. Although the amyloid-like fibrillary aggregates undoubtedly arise in the intracellular or extracellular milieu in many neurodegenerative diseases, the nature of pathogenic aggregate formation and the exact consequences of their accumulation are still not clear. Interestingly, ‘spreading’ of neuropathological changes linked to disease progression has been suggested to result from the intercellular transfer of these pathogenic proteins. Several mitochondrial-associated defects have been extensively researched, including oxidative stress, bioenergetic dysfunction, calcium mishandling (which may result from excitotoxic stimuli and/or stress of the endoplasmic reticulum) or intrinsic apoptosis. In some diseases the misfolded proteins have been even considered as ‘mitochondrial toxins’, since they directly interfere with the organelle. Moreover, there are some controversies concerning the evidence for classical apoptosis in many neurodegenerative diseases. Mitochondrial dysfunction has been also linked to transcription deregulation through disruption of the transcriptional co-activator peroxisome proliferator activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha). Moreover, sirtuins (NAD+-dependent protein deacetylases) have been identified to regulate the crosstalk between aging and neurodegeneration, and both PGC-1alpha and sirtuins seem to be important targets for therapeutic intervention. Indeed, these are signaling pathways induced by calorie restriction, which may have a neuroprotective and preventive role against neurodegeneration. Additionally, hypothalamic dysfunction and neuroendocrine changes governing metabolic abnormalities may be also important features in several neurodegenerative disorders. Despite increased speed of research in many neurodegenerative disorders over the last years, clinical trials focusing on metabolic strategies have yielded many disappointing results. This opened up a series of questions: i) Are metabolic changes secondary to disease onset and progression? ii) Are tested doses and/or drug protocols not well designed? iii) Are there alternative therapeutic targets that deserve more intensive research before being considered for clinical trials? and/or iv) Should we consider multiple pathological targets and thus treatment with more that one drug in future trials? Although the answers to all these questions are far from being reached, it is hoped that a greater understanding of these processes and their role(s) in disease onset and progression will lead to new treatments in the future.