Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity.

Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity.

Publication date: Sep 04, 2019

Accumulative aggregation of mutant Huntingtin (Htt) is a primary neuropathological hallmark of Huntington’s disease (HD). Currently, mechanistic understanding of the cytotoxicity of mutant Htt aggregates remains limited, and neuroprotective strategies combating mutant Htt-induced neurodegeneration are lacking. Here, we show that in Drosophila models of HD, neuronal compartment-specific accumulation of mutant Htt aggregates causes neurodegenerative phenotypes. In addition to the increase in the number and size, we discovered an age-dependent acquisition of thioflavin S, amyloid-like adhesive properties of mutant Htt aggregates and a concomitant progressive clustering of aggregates with mitochondria and synaptic proteins, indicating that the amyloid-like adhesive property underlies the neurotoxicity of mutant Htt aggregation. Importantly, nicotinamide mononucleotide adenylyltransferase (NMNAT), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD) synthase and neuroprotective factor, significantly mitigates mutant Htt-induced neurodegeneration by reducing mutant Htt aggregation through promoting autophagic clearance. Additionally, Nmnat overexpression reduces progressive accumulation of amyloid-like Htt aggregates, neutralizes adhesiveness, and inhibits the clustering of mutant Htt with mitochondria and synaptic proteins, thereby restoring neuronal function. Conversely, partial loss of endogenous Nmnat exacerbates mutant Htt-induced neurodegeneration through enhancing mutant Htt aggregation and adhesive property. Finally, conditional expression of Nmnat after the onset of degenerative phenotypes significantly delays the progression of neurodegeneration, revealing the therapeutic potential of Nmnat-mediated neuroprotection at advanced stages of HD. Our study uncovers essential mechanistic insights to the neurotoxicity of mutant Htt aggregation and describes the molecular basis of Nmnat-mediated neuroprotection in HD.

Zhu, Y., Li, C., Tao, X., Brazill, J.M., Park, J., Diaz-Perez, Z., and Zhai, R.G. Nmnat restores neuronal integrity by neutralizing mutant Huntingtin aggregate-induced progressive toxicity. 06669. 2019 Proc Natl Acad Sci U S A.

Concepts Keywords
Adenine Branches of biology
Adhesive Neurology
Amyloid Neurodegeneration
Autophagic Neuroscience
Clustering Senescence
Conditional Huntingtin
Cytotoxicity Neuroprotection
Drosophila Amyloid
Endogenous Autophagy
Evolutionarily Conserved HTT
Huntingtin Huntington’s disease
Huntington
Mitochondria
Mutant
NAD
Neurodegeneration
Neurodegenerative
Neuropathological
Neuroprotection
Neuroprotective
Neurotoxicity
Nicotinamide
Phenotypes
Progressive
Sci
Synaptic
Toxicity

Semantics

Type Source Name
drug DRUGBANK Nadide
drug DRUGBANK Nicotinamide Mononucleotide
disease DOID neurotoxicity
gene UNIPROT SLC6A4
gene UNIPROT HTT
gene UNIPROT NMNAT1

Original Article

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