Mutation of Ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A prominent feature of Ubqln2-associated diseases is protein aggregation which has been reproduced in our Ubqln2 transgenic and knockin rats. Our preliminary studies show that overexpression of both mutant and wildtype Ubqln2 causes neuron death in transgenic rats, suggesting that excess in normal Ubqln2 is toxic to neurons. Ubqln2 expression must be tightly regulated. To dissect the mechanisms by which pathogenic Ubqln2 causes neurodegeneration, we have created Ubqln2 knockin rats in which a pathogenic mutation is introduced to the Ubqln2. Our Ubqln2 knockin rats differ from the wildtype littermates only in a single nucleotide examined. Therefore, any phenotypes detected in the knockin rats must result from the pathogenic mutation introduced. Using the unprecedented rat models, we will determine how mutant Ubqln2 impacts cellular functions to cause neurodegeneration. We will also examine how Ubqln2 is tightly regulated to maintain its normal levels and thus to avoid its excess in production. By these assays, we will attempt to unravel a mechanism underlying Ubqln2-associated neurodegeneration in the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS095972-02
Application #
9210129
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$307,125
Indirect Cost
$110,250
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Huang, Bo; Wu, Qinxue; Zhou, Hongxia et al. (2016) Increased Ubqln2 expression causes neuron death in transgenic rats. J Neurochem 139:285-293
Deng, Han-Xiang; Shi, Yong; Yang, Yi et al. (2016) Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet 48:733-9