Download Modifier genes in Huntington`s desease - Ruhr

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Summary and conclusions
HD is a devastating, adult-onset, neurological disorder affecting the brain and CNS. Despite
the fact that HD is caused by an abnormal CAG repeat expansion, there is a marked
variability in the severity of symptoms as well as in the AO. This variability in clinical
manifestations and especially the AO is influenced by variations in modifier genes. Although
currently there is no disease modifying treatment for HD, understanding the molecular and
cellular events underlying the neurodegeneration in HD will be crucial for the development of
rational treatment in the future. Analyses of twenty-six candidate genes are described here.
The main goal of the study was finding new AO associations in carefully chosen candidate
genes which are involved in mitochondrial functions and partially, evaluating previously
reported associations. Three previously reported SNPs from the ADORA2A, HAP1 and OGG1
genes were analysed. No association was found for OGG1. For HAP1 modest evidence for
association with the same risk allele as in the original cohort and mAO was detected.
Furthermore, the previously reported association between the original ADORA2A
polymorphism was replicated when the earliest AO data were used. In addition, new
associations in the same gene were identified, thus further supported the potential
contributions of ADORA2A polymorphisms to the complex pathogenesis of HD.
In analyses of new candidate genes, polymorphisms in the PGC-1α gene were genotyped.
Recent data indicate inhibition of PGC-1α function by mHTT, supporting a link between
transcriptional deregulation and mitochondrial dysfunction in HD. In our HD cohort, a
polymorphism located within intron 2, a potential recombination hot spot, explained a small,
but statistically significant amount of the variability in AO. Further analyses were performed
on variations in PGC-1α down-stream effectors, including PGC-1β, NRF-1, NRF-2, PPAR-γ,
ERRα, MFN2 and TFAM as well as SIRT1 as an upstream modulator of PGC-1α function.
Here, variations within the nuclear respiratory factor 1 gene, NRF-1 and the mitochondrial
transcription factor A encoded by TFAM were significantly associated with AO of HD.
Additionally, mtDNA content was compared with various clinical and genetic parameters of
the HD patients. Yet, mtDNA contents in each group were not associated with age, sex, AO,
disease duration, CAG repeat length or any other genotype.
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Finally, in order to evaluate whether mitochondrial mtDNA variation contributes to HD
phenotype, thirteen SNPs that define the major European mtDNA haplogroups were analysed.
Genotype-dependent functional effects on intracellular ATP concentrations were assessed in
peripheral leukocytes. In patients carrying the most common haplogroup H (48.3%), a
significantly lower AO demonstrated and intracellular ATP concentrations in these patients
were significantly higher in comparison to non-H individuals. These data suggest that an
evolutionarily advantageous mitochondrial haplogroup is associated with functional
mitochondrial alterations and may modify the disease phenotype in the context of
neurodegenerative conditions such as HD. Interestingly, PGC-1α, NRF-1, TFAM and
haplogroup H, in combination, explain more variability in AO than isolated analysis.
Altogether, these genotype variations explain about 4.12 % additional variance in AO.
Altogether, this project investigated and identified genetic variations associated with
mitochondrial function and biogenesis. The interplay between mitochondrial and nuclear
encoded genes in modification of AO has revealed novel aspects concerning the genetic basis
of mitochondrial failure in HD. These results further support a better understanding of the
nucleo-mitochondrial signaling and consequently, the role of mitochondria in HD
pathogenesis. Yet, further research on other nuclear-encoded genes would be necessary.
Moreover, since the functional significance of these SNPs are not known yet, understanding
the mechanisms by which DNA variation influence diseases appearance would be one of the
major tasks in future research. Understanding how these polymorphisms interact with each
other to promote systemic metabolic disturbances relevant to the pathogenesis of HD and to
modify AO of disease also has to be considered. This could open the way to designing
personalized intervention strategies to increase the health and well-being of individuals, to
delay the AO and slow down the disease progression.
As this study revealed mitochondril haplogroups, variations in PGC-1α and its downstream
transcription factors can modify the AO of HD with potential underlying alterations in
metabolic properties of the tissues; therefore, PGC-1α pathways could represent as novel
targets for therapeutic intervention.
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