The genetics of dementias. Part 1: Molecular basis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
Journal Title: Advances in Hygiene and Experimental Medicine - Year 2009, Vol 63, Issue
Abstract
Frontotemporal dementia (FTD), characterized by neurodegeneration mainly in the frontal and temporal lobes, accounts for ca. 10–15% of all dementias. In 1892 the Czech-German neuropsychiatrist Arnold Pick reported the first case of FTD in a 71-year-old patient suffering from progressive dementia, memory disturbances, and aphasia associated with frontal and temporal lobe atrophy and the presence of neuronal inclusions. Later the inclusions were named Pick bodies. The neuropathological hallmark of FTD is very differentiated. In contrast to Alzheimer’s disease (AD), there are neither senile plaques nor neurofibrillary tangles in the brains of FTD patients. Frontotemporal dementias are tauopathies, a group of disorders caused by aberrant metabolism of tau protein, a family of proteins associated with microtubules (MAPT: macrotubule-associated tau protein). In the nervous system the protein stabilizes microtubules in neuronal axons and is thus responsible for crucial processes in neuron metabolism, such as signal transduction, plasticity, and intracellular transport. In the human brain, six isoforms are produced from the MAPT gene (chromosome 17 q21.2) by alternative mRNA splicing. The isoforms differ in the number of amino acids in the protein chain, the presence of three (3R tau type) or four (4R tau type) domains responsible for binding to microtubules, and one or two inserts containing from 29 to 58 amino acids. The isoforms are modified posttranslationally by hyperphosphorylation, glycation, or oxidation, which can change the protein’s properties and disturb its normal function. Altered metabolism of tau protein changes its interactions with tubulin, leading to destabilization of the microtubule structure and initiating the generation of toxic tau aggregates. The first mutations in the MAPT gene responsible for frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) were found in 1998. So far over 40 mutations in the MAPT gene have been identified, mainly in families with autosomal dominant FTDP-17 but also in sporadic families with Pick’s disease and AD. The known DNA changes have been classified according to their molecular effects into at least two groups: mutations that change the biochemical properties of tau protein and mutations that alter the alternative splicing of mRNA and lead very often to the overproduction of the 4R tau isoform. The imbalance in the ratio of the synthesized 3R and 4R tau isoforms stimulates protein aggregation and initiates neurodegeneration, leading to the development of dementia.
Authors and Affiliations
Anna Kowalska
Keywords
Related Articles
- EP ID EP66343
- DOI -
- Views 194
- Downloads 0
Mechanisms of cancer angiogenesis
The early stages of tumor growth are independent of blood vessels. When a tumor reaches a volume of approximately 2 mm3, it requires an oxygen and nutrient supply, like other tissues. Satisfaction of the metabolic deman...
The role of metallothionein in oncogenesis and cancer treatment
Metallothionein is cysteine-rich low molecular mass protein. The involvement of MT in many physiological and pathophysiological processes such as apoptosis, proliferation, angiogenesis, and the detoxification of heavy me...
Diabetic microangiopathy in capillaroscopic examination of juveniles with diabetes type 1
Introduction: The aim of this work was a quantitative and qualitative assessment of a selected part of the microcirculation in children with diabetes type 1 using videocapillaroscopy technique. Material/Methods: The auth...
Neuropeptides Y, YY, PP and their clinical significance
peripheral nervous system. Considering the structure and evolutionary origin, neuropeptideY (NPY) is a peptide of the same family as peptide YY (PYY) and pancreatic polypeptide(PP). These proteins were discovered relativ...
HCMV infections after hematopoietic stem cell transplantation – diagnostic methods and importance of viral DNA level monitoring
HCMV infection is very common. The virus infects 30-90% of population. In immunocompromised patients effective elimination of the virus by immune system is limited by immunosuppressive therapy. Active hCMV infection afte...