Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)

By Sarika Garg

FTDP-17 is a group of familial neurodegenerative Tauopathies characterized by diverse but overlapping clinical and neuropathologic features. According to several reports on clinical and neuropathologic features of FTDP-17, three major clinical syndromes have been delineated. These syndromes are disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC), pallid-ponto-nigral degeneration (PPND), and familial multiple system tauopathy with presenile dementia (MSTD). The clinical characteristics of these FTDP-17 Tauopathies variably include memory and language impairments, behavioral and psychiatric abnormalities, extrapyramidal signs, and motor deficits. However, all FTDP-17 brains from affected patients share a common neuropathology characterized by abundant neuronal and to a lesser extent glial fibrillary lesions composed of hyperphosphorylated Tau proteins and are associated with a remarkable loss of neurons in affected regions. 

Autosomal dominant inheritance of these FTDP-17 syndromes suggested that one or more genetic mutations might be pathogenic for these disorders, and linkage analyses showed co-segregation of disease with a genetic locus on chromosome 17q21.1. Since pathologic hallmarks of these disorders are Tau lesions and Tau gene resides within the disease locus of chromosome 17, Tau gene is an obvious candidate for pathogenic mutations in FTDP-17 kindreds. More than 40 different mutations in Tau gene are known to occur in FTDP-17.

Fig.: Tau mutations that result in frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17) map primarily to exons 9-12 or to the intronic region between exons 10 and 11.

In FTDP-17, two mechanisms have been proposed to mediate the effects of mutations in Tau gene. The first mechanism involves perturbations of the alternative splicing of exon 10 resulting change in the ratio of 4R:3R Tau. These mutations comprise a mixture of coding changes, within exon 10 (N279K, delK280, L284L, N296N/H, delN296, P301L/S, G303V, and S305S/N) and also intronic mutations close to the 5’ splice site of exon 10 (at positions +3, +11, +12, +13, +14, +16, +19, and +29). The second mechanism suggests that coding mutations (missense and deletions) directly cause deficits in the abilities of Tau to bind with microtubules (MTs) and promote assembly and stability of MTs. This has been linked to several Tau gene missense mutations including: G272V, delK280, P301L, P301S, V337M, G389R, and R406W using in vitro studies. Tau filaments formation is enhanced by heparin using recombinant G272V, P301L, V337M, and R406W mutant Tau proteins compared to wild type Tau protein. Moreover, mutations in exons other than those in exon 10 (V337M and R406W) promote Tau aggregation which is composed of all six isoforms, whereas other exon 10 mutations (P301L) increase 4R Tau in insoluble FTDP-17 brain fractions. Mutations in the intronic sequence adjacent to the stem loop structure in exon 10 have been identified that alter Tau splicing to increase soluble 3R Tau, leading to increased Tau proteolysis and neuronal apoptosis without deposition of insoluble Tau aggregates.

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