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.