Abstract Details

Title Characterization of a Novel Mitofusin 2 Knock-In Mouse Model

Topic Peripheral Nerve

Presentation(s) P05 - (-)

Poster/Presentation
Number 061

Objective

Background BACKGROUND: CMT comprises a group of heterogeneous peripheral axonopathies affecting 1 in 2,500 individuals. While mutations in several genes cause axonal degeneration in CMT, mitofusin 2 (MFN2) variants account for 91% of the most severe cases of the disease; making it the single most important cause of inherited peripheral axonal degeneration. MFN2 is an integral mitochondrial outer membrane protein that plays a major role in mitochondrial fusion and motility, however, the mechanism by which dominant mutations in this protein lead to neurodegeneration is still unknown.

Design/Methods DESIGN/METHODS: We have generated a MFN2 knock-in mouse strain containing the R94W mutation originally identified in several CMT families. We have performed behavioral, morphological, cell biological, and biochemical studies to characterize the consequences of this mutation.

Results RESULTS: In mice, homozygous inheritance of this mutation leads to a 10% decrease in birth weight (p<.005), followed by death within a day, although the mice appear otherwise healthy. Thorough pathological assessment has not yet identified the cause of perinatal death. At 17 months, heterozygous mice show a >20% decrease in distance traveled and a >30% decrease in vertical movement (p<.05). Heterozygous and homozygous mouse embryonic fibroblasts also show fragmented instead of elongated mitochondrial morphology compared to wild type mice. Homozygous tissues show significantly decreased mitochondrial DNA and ATP amounts.

Conclusions CONCLUSIONS: Although the behavioral heterozygote phenotype is mild, it mimics the human phenotype, with late onset movement deficits, which we are currently trying to enhance using the chemotherapeutic agent vincristine, known to trigger the disease in otherwise asymptomatic patients. Our results thusfar indicate both behavioral and molecular mitochondrial abnormalities, including DNA, ATP, and fusion deficiencies, in MFN2-R94W mice. This model could become a useful tool in future preclinical trials.

Authors/Disclosures
Alleene Strickland PRESENTER	No disclosure on file
Adriana Rebelo	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Andrew Lee	No disclosure on file
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.

��ɫ��

��ɫ��