Genetics and molecular pathology of frontotemporal lobar degeneration

Tetsuaki Arai^{1, 2)}, Masato Hosokawa²⁾, Takashi Nonaka³), Masato Hasegawa³⁾, Haruhiko Akiyama²⁾, Takashi Asada¹⁾

¹⁾Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba
²⁾Department of Dementia and Higher Brain Function, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science
³⁾Dementia Research Project, Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science

Frontotemporal lobar degeneration (FTLD) is a clinical syndrome characterized by behavioral and language difficulties, which refers to a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative disorders. Familial FTLD has been linked to mutations in several genes:the microtubule-associated protein tau (MAPT), granulin (GRN), valosin-containing protein (VCP), TAR DNA-binding protein of 43 kD (TARDBP), fused in sarcoma (FUS), charged multivescicular body protein 2B (CHMP2B), and Chromosome 9 open reading frame 72 (C9ORF72). The associated neuropathology is characterized by selective degeneration of the frontal and temporal lobes with the neuronal and glial inclusions. The current classification of FTLD neuropathology is based on the major constituent protein of them:tau, TAR DNA-binding protein of 43 kD (TDP-43), and FUS. Abnormal phosphorylation, ubiquitination, and proteolytic cleavage are the common pathologic signature of tau and TDP-43 accumulated in diseased brains. Recent findings of mutations in TARDBP, FUS, VCP and C9ORF72 genes in FTLD and ALS cases reveal that FTLD and ALS share a common mechanism of neurodegeneration. This review focuses on the current understanding of genetics and molecular pathology of FTLD, and their relevance to the development of the diagnostics and therapeutics.

Address correspondence to Dr. Tetsuaki Arai MD, PhD, Department of Neuropsychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba(1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan)