What molecules are involved in Huntingtons disease

HUMANGENETICS

research

Other genetic factors influencing Huntington's disease

In addition to the neuronal dysfunction and degeneration, which are ultimately reflected in the motor symptoms of Huntington's disease (MH), those affected also show less specific manifestations, which can sometimes be detected as psychiatric and mental changes many years before clinical diagnosis. Thus, the CAG extension in the Huntingtin-Gen (HTT) a lifelong process, the early stages of which are only gradually recorded and which later lead to a clinical diagnosis. One goal of Huntington's disease research is to create the basis for new therapeutic approaches, also from the point of view that different modifiers are likely to work in all stages of the disease.

It has long been known that the occurrence of the first symptoms is statistically associated with the length of the CAG blocks, so a general statement applies: the longer the CAG block, the earlier the disease manifests itself. However, it is unlikely that two people with the same CAG block length, at exactly the same age will show initial symptoms, have identical impairments, or have exactly the same disease course. The variability is particularly great in the range of lengths of 40-45 CAGs. Differences in the age of first illness can be up to 30 years with the same CAG length. Because of this high variability, so-called modifying genes that influence the MH symptoms were discussed years ago. Of course, environmental influences also play a modifying role, but family examinations have found a high degree of heredity for the variability in the onset of the disease. A closer examination of these genetic factors can therefore be a decisive indicator for further clarification of the biological processes involved in the development of the disease.

For several years our group has been looking for MH-modifying genes. For this purpose, a large group of clinically particularly well-characterized patients was recorded. Information on the exact time when the first symptoms appeared and on various environmental influences were collected together with the patients and their relatives.

A gene is considered to be disease-modifying if changes in its structure or expression have an impact on the manifestation of the disease. In model systems such as yeast or mice, it is possible to manipulate a relevant gene directly, but this is limited in humans modifier-Search for the naturally occurring sequence variations that vary in different people. The most common form of genetic variability is the single nucleotide polymorphism. single nucleotide polymorphism, SNP). Here, only a single DNA building block is changed within a defined DNA segment. So each person's genetic material contains a unique SNP pattern.

How do you know which SNPs should be examined? The preferred approach is the so-called candidate gene approach, in which SNPs are examined in genes that are involved in various signaling pathways and processes that suggest a role in MH. In the further course of the investigation, SNPs in these genes are then associated with a certain appearance, i.e. in the present example the age at the onset of the first motor impairment. For this purpose, the data of many patients, such as CAG length and age of manifestation of MH in different genotypes, are compared (see figure). Whether there are relationships between the genetic makeup and appearance is first clarified using statistical methods. Using this approach, some MH-modifying genes have already been identified. The most promising candidates so far include genes involved in nerve impulse transmission (GRIK2, GRIN2A, GRIN2B, ADORA2A), the DNA overwrite in mRNA (TCERG1), the transport in the nerve cell (HAP1) and the energy budget (PPARGC1A, mitochondrial haplogroup H, NRF-1 and TFAM).

Given the large number of candidate genes in question and the complex interplay between them, it can be assumed that the search for these genes will remain promising in the future. However, it must be taken into account that all of these examinations involve statistical relationships, the biological or physiological correlate of which is often not yet known and do not allow any conclusions to be drawn about the course of the disease in the individual patient. The reference to the involvement of a certain gene and the subsequent precise characterization as well as its changes at the cellular level, however, leads to an improved understanding of the molecular basis of MH and can thus also contribute in the long term to the identification and characterization of new target molecules for early therapeutic interventions.

Figure: Examination process for the search for genetic modifiers

 

 

Selected publications

  • Arning L, Epplen JT. Genetic modifiers of Huntington’s disease: beyond CAG. Future Neurology 7: 93-109, 2012
  • Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L. PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener 6:32, 2011
  • Taherzadeh-Fard E, Saft C, Wieczorek S, Epplen JT, Arning L. Age at onset in Huntington's disease: replication study on the associations of ADORA2A, HAP1 and OGG1 Neurogenetics 11: 435-9, 2010
  • Arning L, Haghikia A, Taherzadeh-Fard E, Saft C, Andrich J, Pula B, Höxtermann S, Wieczorek S, Akkad DA, Perrech M, Gold R, Epplen JT, Chan A. Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington's disease. J Mol Med 88: 431-6, 2010
  • Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S, Arning L. PGC-1alpha as modifier of onset age in Huntington disease. Mol Neurodegener 4:10, 2009
  • Arning L, Saft C, Wieczorek S, Andrich J, Kraus PH, Epplen JT. NR2A and NR2B receptor gene variations modify age at onset in Huntington disease in a sex-specific manner. Hum Genet 122: 175-82, 2007