Abstract
Controlled management of protein levels and quality is essential for normal cellular function. Specific molecular chaperones and foldases monitor the levels and assist correct folding of proteins. The ubiquitin-proteasome system recognizes and degrades misfolded proteins that can otherwise be harmful to cells. However, when misfolded or aggregated proteins excessively accumulate, they may be sequestered to the microtubule-organizing center to form aggresomes. These may then be removed from cells by autophagocytosis. Abnormal protein accumulation and aggregation is a common hallmark of many neurodegenerative diseases. In a recent study, we provide evidence that specific transcript variants (TVs) of ubiquilin-1, which are genetically and functionally associated to Alzheimer's disease (AD), regulate proteasomal and aggresomal targeting of presenilin-1 (PS1), a key player in AD pathogenesis. Our study together with current data provide interesting implications for ubiquilin-1 and its TVs in the pathogenesis of AD and other neurodegenerative diseases involving abnormal protein aggregation.