Morris, Huw Rees; (2002) Molecular genetic analysis of tau related neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tau protein is deposited as neurofibrillary tangles in Alzheimer's disease and in a range of other neurodegenerative diseases, designated tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), some forms of frontotemporal dementia (FTD) and the parkinsonism dementia complex of Guam (PDC). The role of the tau gene in these conditions is analysed, using molecular genetic techniques. In a series of British patients PSP is associated with the tau A0 allele and the A0 allele occurs on a segment of genetic variability designated the HI haplotype, spanning 100 kb of DNA. PSP is not associated with genetic markers flanking tau and is not associated with variability in ApoE or α-synuclein. Clinically diagnosed FTD, and pathologically diagnosed PiD and Parkinson's disease are not associated with tau. Neither ApoE nor tau has any effect on the age at onset of PSP. Cases of pathologically diagnosed PSP with atypical clinical presentations and atypical tau protein deposition patterns have a lower frequency of the tau PSP susceptibility haplotype. Tau was sequenced in 22 families with FTD of whom 11 had mutations in tau: exon 10 +14, exon 10 +16 and the P301S mutation. Pathologically the FTD cases were split into FTD with tau inclusions, FTD with ubiquitin inclusions and FTD lacking distinctive histopathology. The presence of tau mutations correlated with the presence of tau pathology. In general, pathologically defined PiD cases did not have tau mutations, however two individuals with the G398R mutation were identified. Both of these cases had atypical immunohistochemical characteristics. In general, PSP cases did not have tau mutations although one young onset individual clinically diagnosed to have PSP was identified to have a tau exon 10+16 mutation. The clinical and pathological features of amyotrophic lateral sclerosis (ALS) and PDC on Guam were analysed. PDC shares clinical similarities with PSP and other tauopathies. PDC and ALS usually appear as separate clinical and pathological entities. A genome wide association study of PDC was carried out which provided evidence for the association of PDC with chromosome 14 and chromosome 20. These regions will need to be investigated in a second data set and evaluated in a family based study before their significance can be determined.

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