The past year has seen a number of significant advances in our understanding of the neuropathological and molecular genetic basis of
frontotemporal lobar degeneration (
FTLD). Whereas, in the past, most attention focused on
FTLD associated with tau-based pathology and
microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau
FTLD.
FTLD with tau-negative, ubiquitinated inclusions (
FTLD-U) is now recognized as the most common pathology associated with clinical
FTLD. Mutations in the
progranulin gene (PGRN) have been identified as the cause of
FTLD-U linked to chromosome 17. A rapidly growing number of PGRN mutations have been identified, and to date, all appear to cause
FTLD by reducing the amount of functional PGRN
protein (haploinsufficiency). The neuropathology associated with each of the known non-MAPT
FTLD genes and loci (PGRN,
valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of
FTLD-U. The ubiquitinated pathological
protein in
FTLD-U has been identified as TAR
deoxyribonucleic acid-
binding protein with M (r) 43 kDa (TDP-43). Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of
FTLD-U and related conditions. It is anticipated that these discoveries will facilitate the development of new diagnostic tests and
therapeutics.