Frontotemporal lobar degeneration (
FTLD) is the most common cause of
dementia with pre-senile onset, accounting for as many as 20% of cases. A common subset of
FTLD cases is characterized by the presence of ubiquitinated inclusions in vulnerable neurons (
FTLD-U). While the pathophysiological mechanisms underlying neurodegeneration in
FTLD-U have not yet been elucidated, the presence of inclusions in this disease indicates enhanced aggregation of one or several
proteins. Moreover, these inclusions suggest altered expression, processing, or degradation of
proteins during
FTLD-U pathogenesis. Thus, one approach to understanding disease mechanisms is to delineate the molecular changes in
protein composition in
FTLD-U brain. Using a combined approach consisting of
laser capture microdissection (LCM) and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 1252
proteins in hippocampal dentate granule cells excised from three post-mortem
FTLD-U and three unaffected control cases processed in parallel. Additionally, we employed a labeling-free quantification technique to compare the abundance of the identified
proteins between
FTLD-U and control cases. Quantification revealed 54
proteins with selective enrichment in
FTLD-U, including TAR-
DNA binding protein 43 (TDP-43), a recently identified component of ubiquitinated inclusions. Moreover, 19
proteins were selectively decreased in
FTLD-U. Subsequent immunohistochemical analysis of TDP-43 and three additional
protein candidates suggests that our proteomic profiling of
FTLD-U dentate granule cells reveals both inclusion-associated
proteins and non-aggregated disease-specific
proteins. Application of LCM is a valuable tool in the molecular analysis of complex tissues, and its application in the proteomic characterization of
neurodegenerative disorders such as
FTLD-U may be used to identify
proteins altered in disease.