Current Genomics (v.15, #1)

Parkinson's disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years,advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps comingfrom genetic studies, including genome-wide association approaches. These large scale studies allow the identification ofgenomic regions harboring common variants associated to disease risk. Since the first genome-wide association study onsporadic Parkinson's disease performed in 2005, improvements in study design, including the advent of meta-analyses,have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familialPD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci(SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggestthat more loci are still to be discovered. Additional association studies combined with deep re-sequencing of knowngenome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each ofthese associated genes and variants are identified they will give insight into the biological pathways involved the etiologyof Parkinson's disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosisand as targets for the development of better, personalized treatment.

Molecular Effects of L-dopa Therapy in Parkinsonµs Disease by Jolanta Dorszewska, Michal Prendecki, Margarita Lianeri, Wojciech Kozubski (11-17).
Parkinson's disease (PD) is one of the most common neurological diseases in elderly people. The mean age ofonset is 55 years of age, and the risk for developing PD increases 5-fold by the age of 70. In PD, there is impairment inboth motor and nonmotor (NMS) functions. The strategy of PD motor dysfunction treatment is simple and generally basedon the enhancement of dopaminergic transmission by means of the L-dihydroxyphenylalanine (L-dopa) and dopamine(DA) agonists. L-dopa was discovered in the early -60's of the last century by Hornykiewicz and used for the treatment ofpatients with PD. L-dopa treatment in PD is related to decreased levels of the neurotransmitter (DA) in striatum and absenceof DA transporters on the nerve terminals in the brain. L-dopa may also indirectly stimulate the receptors of the D1and D2 families. Administration of L-dopa to PD patients, especially long-time therapy, may cause side effects in theform of increased toxicity and inflammatory response, as well as disturbances in biothiols metabolism. Therefore, in PDpatients treated with L-dopa, monitoring of oxidative stress markers (8-oxo-2'-deoxyguanosine, apoptotic proteins) andinflammatory factors (high-sensitivity C-reactive protein, soluble intracellular adhesion molecule), as well as biothiolcompounds (homocysteine, cysteine, glutathione) is recommended. Administration of vitamins B6, B12, and folates alongwith an effective therapy with antioxidants and/or anti-inflammatory drugs at an early stage of PD might contribute toimprovement in the quality of the life of patients with PD and to slowing down or stopping the progression of the disease.

Genetic Variants in Diseases of the Extrapyramidal System by Anna Oczkowska, Wojciech Kozubski, Margarita Lianeri, Jolanta Dorszewska (18-27).
Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognizedthat disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provideclues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to thedetection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and hashelped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in thediagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagnosis.It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments thatmay in the future will result in more effective treatment of such diseases as Parkinson's or Huntington's. Currently usedmolecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxiainherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich's disease, ataxia with oculomotorapraxia,Huntington's disease, dystonia type 1, Wilson's disease, and some cases of Parkinson's disease.

Histone Acetyltransferases in Plant Development and Plasticity by Irina Boycheva, Valya Vassileva, Anelia Iantcheva (28-37).
In eukaryotes, transcriptional regulation is determined by dynamic and reversible chromatin modifications,such as acetylation, methylation, phosphorylation, ubiquitination, glycosylation, that are essential for the processesof DNA replication, DNA-repair, recombination and gene transcription. The reversible and rapid changes in histoneacetylation induce genome-wide and specific alterations in gene expression and play a key role in chromatin modification.Because of their sessile lifestyle, plants cannot escape environmental stress, and hence have evolved a numberof adaptations to survive in stress surroundings. Chromatin modifications play a major role in regulating plant geneexpression following abiotic and biotic stress. Plants are also able to respond to signals that affect the maintaince of genomeintegrity. All these factors are associated with changes in gene expression levels through modification of histoneacetylation. This review focuses on the major types of genes encoding for histone acetyltransferases, their structure,function, interaction with other genes, and participation in plant responses to environmental stimuli, aswell as their role in cell cycle progression. We also bring together the most recent findings on the study of the histoneacetyltransferase HAC1 in the model legumes Medicago truncatula and Lotus japonicus.

Damaged and misfolded proteins accumulate during the aging process, impairing cell function and tissue homeostasis.These perturbations to protein homeostasis (proteostasis) are hallmarks of age-related neurodegenerative disorderssuch as Alzheimer's, Parkinson's or Huntington's disease. Damaged proteins are degraded by cellular clearancemechanisms such as the proteasome, a key component of the proteostasis network. Proteasome activity declines duringaging, and proteasomal dysfunction is associated with late-onset disorders. Modulation of proteasome activity extendslifespan and protects organisms from symptoms associated with proteostasis disorders. Here we review the links between proteasomeactivity, aging and neurodegeneration. Additionally, strategies to modulate proteasome activity and delay the onsetof diseases associated to proteasomal dysfunction are discussed herein.

Systemic Lupus Erythematosus: Old and New Susceptibility Genes versus Clinical Manifestations by J. De Azevedo Silva, C. Addobbati, P. Sandrin-Garcia, S. Crovella (52-65).
Systemic Lupus Erythematosus (SLE) is one of the most relevant world-wide autoimmune disorders. The formationof autoantibodies and the deposition of antibody-containing immune complexes in blood vessels throughout thebody is the main pathogenic mechanism of SLE leading to heterogeneous clinical manifestations and target tissue damage.The complexity of etiology and pathogenesis in SLE, enclosing genetic and environmental factors, apparently is one ofthe greatest challenges for both researchers and clinicians. Strong indications for a genetic background in SLE come fromstudies in families as well as in monozygotic and dizygotic twins, discovering several SLE-associated loci and genes (e.g.IRF5, PTPN22, CTLA4, STAT4 and BANK1). As SLE has a complex genetic background, none of these genes is likely tobe entirely responsible for triggering autoimmune response in SLE even if they disclosure a potentially novel molecularmechanisms in the pathogenesis' disease. The clinical manifestations and disease severity varies greatly among patients,thus several studies try to associate clinical heterogeneity and prognosis with specific genetic polymorphisms in SLE associatedgenes. The continue effort to describe new predisposing or modulating genes in SLE is justified by the limitedknowledge about the pathogenesis, assorted clinical manifestation and the possible prevention strategies. In this review wedescribe newly discovered, as well as the most studied genes associated to SLE susceptibility, and relate them to clinicalmanifestations of the disease.

Interrelation Between Protein Synthesis, Proteostasis and Life Span by Kristin Arnsburg, Janine Kirstein-Miles (66-75).
The production of newly synthesized proteins is a key process of protein homeostasis that initiates the biosyntheticflux of proteins and thereby determines the composition, stability and functionality of the proteome. Protein synthesisis highly regulated on multiple levels to adapt the proteome to environmental and physiological challenges such as agingand proteotoxic conditions. Imbalances of protein folding conditions are sensed by the cell that then trigger a cascadeof signaling pathways aiming to restore the protein folding equilibrium. One regulatory node to rebalance proteostasisupon stress is the control of protein synthesis itself. Translation is reduced as an immediate response to perturbations ofthe protein folding equilibrium that can be observed in the cytosol as well as in the organelles such as the endoplasmaticreticulum and mitochondria. As reduction of protein synthesis is linked to life span increase, the signaling pathways regulatingprotein synthesis might be putative targets for treatments of age-related diseases. Eukaryotic cells have evolved acomplex system for protein synthesis regulation and this review will summarize cellular strategies to regulate mRNAtranslation upon stress and its impact on longevity.