ROLE OF PHARMACOLOGICALLY INDUCED-TFEB IN AGING AND AGE-RELATED NEURODEGENERATION

An important characteristic feature of aging and many age-related neurodegenerative diseases is a loss of protein homeostasis (proteostasis), which is accompanied by increased accumulation of damaged, misfolded and aggregated proteins. One of the vital components of proteostasis, autophagy, mediates the breakdown and recycling of proteins and other cellular components within the lysosome. Our central hypothesis is that age-related dysfunction in autophagy establishes a prodromal process resulting in decreased protein homeostasis which causes neurodegeneration. Age-related failure in autophagy could result from down regulation of transcription factor EB (TFEB), the master regulator of lysosomal biogenesis. This in turn would impact the cell’s ability to process damaged proteins. Recent studies from our labs reported that up-regulation of TFEB by either rapamycin or trehalose prevented neurodegeneration. Encouraged by these results, we conducted a small molecule screen to identify novel candidates that could induce TFEB and its target genes to levels far exceeding than already existing inducers (e.g. rapamycin and trehalose). Since then, we have discovered new class of compounds that gratuitously induce TFEB and its targets and are protective in in vivo proteotoxic models of neurodegenerative diseases. I will be discussing findings related to this study and potential implication of TFEB in preventing aging and age-related neurodegenerative diseases.