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Exp Neurol. 2014 Dec;262 Pt B:75-83. doi: 10.1016/j.expneurol.2013.11.006. Epub 2013 Nov 15.

Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not.

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Reta Lilla Weston Research Laboratories and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. Electronic address:
Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, Division of Neurology, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON M5S 3H2, Canada.


Over the last 5 years, several new genes have been described for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While it has long been clear that there are many kindreds in which the two diseases co-occur, there are also many in which the diseases segregate alone. In this brief review, we suggest that keeping the loci which lead to both diseases separate from those which lead to just one gives a clearer conclusion about disease mechanisms than lumping them together. The hypothesis that this separation leads to is that loci which cause both ALS and FTD affect the autophagic machinery leading to damaged protein aggregation and those which lead to just ALS are mainly involved in RNA/DNA metabolism. Two of the genes causing FTD alone (CHMP2B and GRN) are associated with damaged autophagy/lysosomal pathway. However, the third FTD gene (MAPT) maps to a different pathway, which perhaps is not surprising, since it is associated with a different (not p62-related) brain pathology characterized by abnormal tau filaments. We conclude that the current state of knowledge points to common mechanisms responsible for susceptibilities specific to neuronal classes. This includes the disruption of RNA metabolism in motor neurons and protein clearance, which is common between cortical and motor neurons.


ALS; FTD; Genetics; Pathology

[Indexed for MEDLINE]

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