Abstract Details

Title Dose-Dependent and Mutant Enhanced Neurotoxicity in Mice Expressing Wild Type or ALS-Linked Mutants of FUS/TLS

Topic Anterior Horn

Presentation(s) S06 - (-)

Poster/Presentation
Number 006

Objective

Background Mutations in two ubiquitously expressed nucleic-acid binding proteins, TDP-43 (TAR-DNA binding protein-43 KDa) and FUS/TLS (fused in sarcoma/translocated in liposarcoma), cause amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Abnormal aggregates of these two proteins are present in inherited and sporadic ALS, FTLD, and other neurodegenerative diseases, independent of mutations in either gene.

Design/Methods We used transgene technology, protein and RNA analysis, behavioral and electrophysiological methods to characterize the cohorts of mice expressing wt and ALS-linked mutations in FUS .

Results We show here that broad expression within the nervous system of wild type or either of two ALS-linked mutants of human FUS/TLS produces progressive motor phenotypes, including abnormal gait, glial activation, degeneration of motor and sensory axons, and loss of spinal cord motor neurons, accompanied by denervation-induced muscle fibrillations, all of which are characteristics of ALS.

Conclusions Expression of wild type or ALS-linked mutants of human FUS/TLS downregulates endogenous mouse FUS/TLS expression at both mRNA and protein levels, illustrating an auto-regulation mechanism for FUS/TLS. Furthermore, generation of homozygote or double heterozygotes expressing human wild type FUS/TLS cause rapidly progressive neurological phenotypes and dose-dependent lethality accompanied by widespread neurodegeneration. Taken together, our results demonstrate that (1) mice expressing ALS-linked mutation in FUS/TLS develop earlier progressive motor deficits and early mortality than mice expressing comparable level of wild type human FUS/TLS, and (2) a surprisingly small increase in increased expression of wild type FUS/TLS sharply accelerate neurodegeneration, providing a basis for FUS/TLS involvement in pathogenesis in the absence of mutation.

Authors/Disclosures
Hristelina S. Ilieva, MD (ALS Weinberg Clinic) PRESENTER	The institution of Dr. Ilieva has received research support from ALSA. The institution of Dr. Ilieva has received research support from Strategius. Dr. Ilieva has received personal compensation in the range of $500-$4,999 for serving as a reviewer with ALS Canada. Dr. Ilieva has received personal compensation in the range of $0-$499 for serving as a reviewer with DOD.
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Richard Harris	Richard Harris has nothing to disclose.
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Don Cleveland, PhD (Ludwig Institute)	No disclosure on file

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