Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons

We report that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines in transgenic Caenorhabditis elegans. These effects are dependent on daf-16 (Forkhead). Additionally, resveratrol rescued mutant polyglutamine-specific cell death in neuronal cells derived from HdhQ111 knock-in mice. We conclude that Sir2 activation may protect against mutant polyglutamines.     

Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP

Endoplasmic reticulum (ER) chaperones and ER stress have been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer and Parkinson diseases, but their contribution to neuron death remains uncertain. In this study, we establish a direct in vivo link between ER dysfunction and neurodegeneration. Mice homozygous with respect to the woozy (wz) mutation develop adult-onset ataxia with cerebellar Purkinje cell loss. Affected cells have intracellular protein accumulations reminiscent of protein inclusions in both the ER and the nucleus. In addition, upregulation of the unfolded protein response, suggestive of ER stress, occurs in mutant Purkinje cells. We report that the wz mutation disrupts the gene Sil1 that encodes an adenine nucleotide exchange factor of BiP, a crucial ER chaperone. These findings provide evidence that perturbation of ER chaperone function in terminally differentiated neurons leads to protein accumulation, ER stress and subsequent neurodegeneration.     

Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.     

High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease

Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% +/- 9.3%; individuals with Parkinson disease, 52.3% +/- 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.     

Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.