The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum

Abstract

There is increasing evidence that frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) represent a continuum of neurodegenerative diseases. FTLD is complicated by ALS in a significant proportion of patients, and neuropsychological studies have demonstrated frontotemporal dysfunction in up to 50% of ALS patients. More recently, advances in neuropathology and molecular genetics have started to disclose the biological basis for the observed clinical concurrence. TDP-43 and FUS have been discovered as key pathological proteins in both FTLD and ALS. The most recent discovery of a pathological hexanucleotide repeat expansion in the gene C9orf72 as a frequent cause of both FTLD and ALS has eventually confirmed the association of these two at first sight distinct neurodegenerative diseases. Mutations in the TARDBP, FUS, and VCP genes had previously been associated with different phenotypes of the FTLD-ALS spectrum, although in these cases one end of the spectrum predominates. Whilst on the one hand providing evidence for overlap, these discoveries have also highlighted that FTLD and ALS are etiologically diverse. In this review, we review the recent advances that support the existence of an FTLD-ALS spectrum, with particular emphasis on the molecular genetic aspect.

Figure 1.

A: FTLD and ALS form a clinical disease continuum. B: Molecular relationships between FTLD and ALS. Pathological proteins are indicated in blue, causal genes in yellow. Full lines indicate strong correlations; dotted lines represent putative correlations. Correlations between genes and pathological proteins are indicated by light gray lines.

Figure 2.

TDP-43 proteinopathy in FTLD. Ubiquitin and TDP-43 immunohistochemistry of sections from the superficial frontal cortex (FCx) and temporal cortex (TCx) of a patient with a VCP mutation (176). Frequent intranuclear inclusions (arrow-heads) are seen that stain positive for ubiquitin and TDP-43.