Acquired expression of mutant Mitofusin 2 causes progressive neurodegeneration and abnormal behavior

Abstract

Neurons have high plasticity in developmental and juvenile stages that decreases in adulthood. Mitochondrial dynamics are highly important in neurons to maintain normal function. To compare dependency on mitochondrial dynamics in juvenile and adult stages, we generated a mouse model capable of selective timing of the expression of a mutant of the mitochondrial fusion factor Mitofusin 2 (MFN2). Mutant expression in the juvenile stage had lethal effects. Contrastingly, abnormalities did not manifest until 150 d after mutant expression during adulthood. After this silent 150 d period, progressive neurodegeneration, abnormal behaviors, and learning and memory deficits similar to those seen in human neurodegenerative diseases were observed. This indicates that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. Our findings highlight the need to consider the timing of disease onset in mimicking human neurodegenerative diseases.

Visualizing an convergence of three mitochondrial molecule mRNAs for DRP1/MFN2/UCP4 on soma of cerebellar Purkinje cells by RNAscope

“…The nding of dense distribution of Mfn2 on Purkinje cells deserves high attention for four reasons. First, the mutations in Mfn2 have been found to cause a human neurodegeneration disease, Charcot-Marie-Tooth neuropathy type 2A [29][30][31][32]. Second, our data have supported previous paradigm that Mfn2 is expressed at signi cantly greater levels in Purkinje cells than is Mfn1 [29].…”

Visualizing an convergence of three mitochondrial molecule mRNAs for DRP1/MFN2/UCP4 on soma of cerebellar Purkinje cells by RNAscope

“…The nding of dense distribution of Mfn2 on Purkinje cells deserves high attention for four reasons. First, the mutations in Mfn2 have been found to cause a human neurodegeneration disease, Charcot-Marie-Tooth neuropathy type 2A (Chen H et al, 2007;Züchner S et al, 2004;Chung KW et al, 2006;Ishikawa K et al, 2019). Second, our data have supported previous paradigm that Mfn2 is expressed at signi cantly greater levels in Purkinje cells than is Mfn1 (Chen H et al, 2007).…”

Visualizing a Convergence of Three Mitochondrial Molecule mRNAs for Drp1/Mfn2/Ucp4 on Soma of Cerebellar Purkinje Cells by RNAscope

“…The nding of dense distribution of Mfn2 on Purkinje cells deserves high attention for four reasons. First, the mutations in Mfn2 have been found to cause a human neurodegeneration disease, Charcot-Marie-Tooth neuropathy type 2A [34][35][36][37]. Second, our data have supported previous paradigm that Mfn2 is expressed at signi cantly greater levels in Purkinje cells than is Mfn1 [34].…”