Salvage NAD+ biosynthetic pathway enzymes moonlight as molecular chaperones to protect against proteotoxicity.

Human neurodegenerative proteinopathies are disorders associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) conditions such as Huntington's disease (HD) and α-synucleinopathies such as Parkinson's disease (PD). Overexpression of NMNAT/Nma1, an enzyme in the NAD+ biosynthetic salvage pathway, acts as an efficient suppressor of proteotoxicities in yeast, fly and mouse models.

Exploiting Post-mitotic Yeast Cultures to Model Neurodegeneration.

Over the last few decades, the budding yeast has been extensively used as a valuable organism to explore mechanisms of aging and human age-associated neurodegenerative disorders. Yeast models can be used to study loss of function of disease-related conserved genes and to investigate gain of function activities, frequently proteotoxicity, exerted by non-conserved human mutant proteins responsible for neurodegeneration. Most published models of proteotoxicity have used rapidly dividing cells and suffer from a high level of protein expression resulting in acute growth arrest or cell death.

Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging.

Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which overexpression exerts this protection remains unclear.

Dietary restriction, mitochondrial function and aging: from yeast to humans.

Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways.