Ubiquitin-Proteasome Pathways in Neurodegenerative Diseases

The ubiquitin–proteasome system (UPS) maintains protein homeostasis by tagging damaged or misfolded proteins with ubiquitin and directing them to the proteasome for degradation. In neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, dysfunction of this pathway leads to the accumulation of toxic protein aggregates, synaptic dysfunction and neuronal death. Aberrant ubiquitin signalling, whether through mutations in ubiquitin itself, altered activity of E3 ubiquitin ligases or impaired deubiquitinating enzymes, reduces clearance of key substrates including amyloid precursor protein (APP), amyloid-β peptides and hyperphosphorylated tau. Emerging evidence implicates UPS components not only in the onset and progression of neurodegeneration but also in neuronal recovery after injury. Therapeutic strategies that restore proteasome function or enhance selective ubiquitination show promise for ameliorating proteinopathy, attenuating neuroinflammation and improving cognitive and motor outcomes in preclinical models.

Research from Nature Portfolio

Recent studies have demonstrated that a frameshift variant of ubiquitin, termed ubiquitin B+1 (UBB+1), accumulates early in Alzheimer’s disease and directly drives hallmark pathologies. In a three-dimensional human neural culture, expression of UBB+1 alone induced extracellular amyloid-β deposits and insoluble hyperphosphorylated tau aggregates. Mechanistically, UBB+1 competes with native ubiquitin for binding to the deubiquitinating enzyme UCHL1, leading to impaired removal of ubiquitin from target proteins and consequent buildup of APP and amyloid-β. Importantly, silencing UBB+1 in this model prevented emergence of amyloid and tau pathology, highlighting ubiquitin signalling as a potential therapeutic node for early intervention.

Ubiquitin-Proteasome Pathways in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in ubiquitin-proteasome pathways in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Ubiquitination: The covalent attachment of ubiquitin to a protein substrate, marking it for degradation or altering its function.

Proteasome: A multi-subunit protease complex that recognises ubiquitin-tagged proteins and degrades them into peptides.

Deubiquitinating enzyme (DUB): An enzyme that removes ubiquitin from substrates, regulating protein stability and recycling ubiquitin.

Amyloid-β (Aβ): A peptide derived from APP that aggregates extracellularly to form plaques in Alzheimer’s disease.

Tau: A microtubule-associated protein which, when hyperphosphorylated, forms intracellular neurofibrillary tangles in Alzheimer’s disease.

References

1. Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model. Nature Communications (2023).
2. FBXL16: a new regulator of neuroinflammation and cognition in Alzheimer’s disease through the ubiquitination-dependent degradation of amyloid precursor protein. Biomarker Research (2024).
3. Perturbations of Ubiquitin-Proteasome-Mediated Proteolysis in Aging and Alzheimer’s Disease. Frontiers in Aging Neuroscience (2019).
4. The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer’s Disease and Spinal Cord Injury. Frontiers in Molecular Neuroscience (2016).