Sirtuins: Common Targets in Aging and in Neurodegeneration

Rita      Machado de Oliveira; Teresa      F. Pais; Tiago      Fleming Outeiro

Abstract

Aging has been a subject of interest since primordial times. More recently, it became clear that aging is the major known risk factor for several neurodegenerative disorders, such as Alzheimers disease, Parkinsons disease and Huntingtons disease. A major focus in the field of aging is to examine whether the genetic regulators of lifespan also regulate the trigger and/or progression of age-related disorders. Sirtuins, which belong to the Sir2 family of NAD+-dependent deacetylases, are known to regulate longevity in yeast, worms, and flies. In mammals, there are seven homologs of the yeast Sir2, Sirt1-7. Therefore, the challenge now is to unravel howthe seven mammalian Sir2 proteins communicate to regulate the cross talk between aging and the onset and progression of age-related disorders. Here, we review how sirtuins contribute for aging and, in particular, for neurodegeneration and how they are becoming attractive targets for therapeutic intervention.

Keywords: Neurodegeneration, sirtuins, Parkinson's disease, Alzheimer's disease, therapeutic targets, aging, Sir2 family, NAD+, O-acetyle ADP ribose, Caloric restriction, Inflammatory diseases, Oxidative stress, Protein misfolding, Mitochondrial dysfunction, Huntington's disease, Sir complex, Heterochromatin, rDNA array, C. elegans, Reservatrol, Drosophila, Apoptosis, p53, Ku70, Forkhead transcription factors, CR trials, PGC-1α, Replication, Transcription, Hsf-1, Heat shock proteins, CAG-repeats, PolyQ, Substantia nigra, Lewy bodies, α-synuclein, OHDA, MPTP, High-throughput screenings, Fluorescent biochemical assays, 1,4-dihydropyridine-based derivatives, 2-anilinobenzamide, Carbomido-NAD+, Sirtinol, Kinase inhibitors