Mechanisms of disease in frontotemporal lobar degeneration: Gain of function versus loss of function effects

Glenda Halliday, Eileen H. Bigio, Nigel J. Cairns, Manuela Neumann, Ian R.A. MacKenzie, David M.A. Mann*

*Corresponding author for this work

Research output: Contribution to journalReview article

59 Scopus citations

Abstract

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 5-10 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). Depending on the protein concerned, the signature accumulations can take the form of inclusion bodies (neuronal cytoplasmic inclusions and neuronal intranuclear inclusions) or dystrophic neurites, in the cerebral cortex, hippocampus and subcortex. In some instances, glial cells are also affected by inclusion body formation. In motor neurone disease (MND), TDP-43 or FUS inclusions can present within motor neurons of the brain stem and spinal cord. This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.

Original languageEnglish (US)
Pages (from-to)373-382
Number of pages10
JournalActa Neuropathologica
Volume124
Issue number3
DOIs
StatePublished - Sep 1 2012

Keywords

  • FUS
  • Frontotemporal lobar degeneration
  • Gain of function
  • Loss of function
  • Microtubule associated protein
  • Motor neurone disease
  • TDP-43
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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