In Huntingtons disease a brain region plays surprising role
A research team at the University of Twente has shed light on the upside down role played by an anatomical region of the brain that is often misdiagnosed in patients with Huntingtons Disease. The study has just been published in Cell Reports.
Huntingtons Disease is a fatal neurodegenerative hereditary disease that affects 5-10 per cent of the population worldwide. The neurodegenerative effect of the disease is primarily due to the peroxisome proliferator-activated receptor alpha (PGA-AR) cell signalling pathway. It is known that training animals with a PGA-AR pathway activates the PGRNA but in most cases this protects cancer cells. In the case of the brains of patients suffering from this condition the aberrant signaling pathway of the PGA-AR is completely lost or triggers the disease.
The neuropsychiatric disease is severe affecting approximately 1000 people every week. In the population of young adults with homozygous micro-alleles in the PGRNA gene variant 2A of the PGA-AR receptor is found in the substantia nigra an area that shelters the motor neurons responsible for movement and which in mid-brain is known to be the cradle of the movement learning and memory system.
In this mutation we have a modified trace protein on the non-neuronal PGA-AR that is misfolded into this variant with an abnormal -spondin gene. This study was done in collaboration with partner institutions such as the Netherlands the United Kingdom and the National Institutes for Health Diagnostic Laboratory Repository in Jena. Early gene depletion allowed us to elucidate the role of this variant in the pathogenesis of Huntingtons Disease states Marjan Elsterd Associate Professor at the Biobank Research Group on Pathogenesis and Head of the Structural Functional Models and Applications Research in Statins Neurosciences.
Peroxisome proliferator-activated receptors are known to stimulate the proliferation of certain types of cells. Among the most recognized defects in this family are accumulation of the toxic protein tyrosine hydroxymethyltyrosine (TT) in the mouse striatum in the presence of 15-20 per cent brain hypoplasia (BDH) which is a neonatal cerebral anomaly a disease of unborn children and defects of the two major somatic mutations in this family such as ADHN1 and HDN-L (HN-L). BDH is caused by a moderate genetic mutation that occurs in the amino acid tyrosine (T) for which there is no replication in the mouse. TDH occurs more frequently in children which is why the study had to seek some other explanation of the source of the difference in accumulation. During the detailed proteomics and microcomputed tomography (CT) brain scans there were no any changes in the levels of TTTTN (phenotype) in patients and healthy control subjects. This finding suggests a birth defect in this family which may account for the relatively frequent incidence of dysmorphology and mutations in this family of mutations within the disease spectrum states Dr. Elsterd.
The study was conducted by research teams from the universities of Twente Dekkers and Copenhagen together with the Leibniz Research Institute for Genomics and Microbiometrys Svalbard Research Site.