Chapter

Neuropathology of frontotemporal lobar degeneration

Nigel J. Cairns

in Amyotrophic Lateral Sclerosis and the Frontotemporal Dementias

Published on behalf of Oxford University Press

Published in print October 2012 | ISBN: 9780199590674
Published online November 2012 | e-ISBN: 9780191753466 | DOI: http://dx.doi.org/10.1093/med/9780199590674.003.0018
Neuropathology of frontotemporal lobar degeneration

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The accumulation of misfolded proteins in inclusion bodies is a common feature of a wide variety of sporadic and familial neurodegenerative disorders that present clinically with FTD. These diseases are distinguished by the distinct topographic and cell type-specific distribution of inclusions. The biochemical and ultrastructurally characteristics of the inclusions also reveal a significant phenotypic overlap. The discovery of multiple mutations in the MAPT, GRN, C9ORF72, TARDBP, VCP, and FUS genes leading to abnormal filamentous inclusions demonstrates that neuronal and glial dysfunction is sufficient to produce neurodegenerative disease. Experimental evidence indicates that mutations lead to specific alterations in expression, function, and biochemistry of tau, progranulin, TDP-43, VCP, and FUS proteins. Similarly, mutations in CHMP2B result in misfolding, protein aggregation, ubiquitination of inclusions, and neurodegeneration in FTLD with CHMP2B mutation. The identification of gene mutations in FTLD or polymorphisms at distinct genetic loci that either cause or are risk factors for disease will provide additional insights into disease pathogenesis as well as in the development of new models and novel strategies for treatment and prevention.

Chapter.  17148 words.  Illustrated.

Subjects: Neurology ; Pathology

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