Matt Wohlever

A hallmark of Alzheimer’s Disease and Related Dementias (ADRDs) is defects in proteostasis. Ubiquilins are a family of proteins that serve as a major hub in the proteostasis network and are also intimately linked with ADRDs. For example, single point mutations in Ubiquilins lead to Amyotrophic Lateral Sclerosis (ALS). Despite the clear medical relevance, the underlying mechanisms of Ubiquilin function are not understood at the molecular, subcellular, and neuronal levels, which presents a significant barrier to developing targeted therapeutics to treat ADRDs. Paradoxically, while Ubiquilins are traditionally thought to shuttle proteins to the proteasome for degradation, there are many reports in the literature of Ubiquilins stabilizing client proteins, including many ADRD proteins. It is unclear how this triage decision is made and executed.

We have recently discovered that Ubiquilins directly bind to ADRD proteins via the Sti1 domain and recruit E3 ligases to promote the formation of biomolecular condensates that protect substrates from degradation (Fig 1). This contrasts with the existing model, which posits that Ubiquilins interact with ubiquitinated proteins via the UBA domain and then shuttles these proteins to the proteasome for degradation. The new paradigm of Ubiquilins as molecular chaperones that stabilize ADRD proteins via the formation of condensates will fundamentally shift our approach for developing therapeutic interventions in Alzheimer’s Disease and Related Dementias.