Frontotemporal dementia (FTD) is a common aging-related neurodegenerative disease and shares a wide
spectrum of clinical, pathological, and genetic features with amyotrophic lateral sclerosis (ALS). Recent advance
in genetics study indicates that pathogenic mutations of most ALS genes are also causative to FTD. Substantial
evidence from genetics study suggests Ubqln2 as a causative gene of both ALS and FTD, but how Ubqln2
causes the diseases is not known. Overexpression of Ubqln2 with or without a pathogenic mutation causes
indistinguishable phenotypes reminiscent of ALS and FTD, suggesting that pathogenic mutation or excess
expression of Ubqln2 is both pathogenic for the diseases. As deletion of the Ubqln2 in knockout rodents does
not affect neuronal function, pathogenic Ubqln2 likely causes the diseases through a gain of unknown function.
A prominent feature of Ubqln2 related diseases is protein aggregation, which is well reproduced in transgenic
rodents overexpressing Ubqln2. Using biochemical approaches, we attempt to unravel how pathogenic Ubqln2
induces neuronal dysfunction via its gained aggregation-prone feature. Our preliminary studies observed that
Ubqln2 is deregulated in FTD patients and at miRNA deficiency. The proposed research will determine how
deregulated Ubqln2 expression is related to impaired cognitive function and neuronal death in novel rat models
and how miRNA deficiency leads to deregulated Ubqln2 expression and to cortical dementia in the diseases.
Upon completion, the proposed research will gain a mechanistic insight on Ubqln2 related diseases and likely
will identify a network of genes essential to neuronal survival and cognitive function.