Mutations or environmental stresses lead to misfolded proteins in neurons and other cells. Misfolded or aggregated proteins must be removed immediately or degraded by the ubiquitin proteasome system (UPS). Decades of research have shown that inability to respond to misfolded protein is the major cause of neurodegeneration.
Aggregated proteins or proteinopathies perturb mitochondrial function, leading to damaged mitochondria and loss of energy and ultimately death of a cell or neurons. Defects in mitochondrial health accumulate as we age, leading to a wide variety of pathologies including neurodegeneration. Ubiquitin ligases mark damaged mitochondria for degradation (mitophagy) and generation of new mitochondria (mitobiogenesis).
The Ubiquitin-proteasome system (UPS) dysfunction is a key factor in the development of Parkinson’s disease (PD). Pathogenic PD proteins such as alpha-synuclein have been shown to be ubiquitylated by E3 ligases and degraded by the proteasome, and dysfunction of specific UPS proteins has been implicated in familial PD.
UPS dysfunction is particularly damaging to neuronal cells because these cells are particularly reliant on protein quality control for their survival. The details of these alterations may include changes in the ubiquitin chain linkages that redirect the fate of the ubiquitylated proteins.
Systemic and neurological symptoms resulting from cellular quality control failure and dopaminergic loss.
Correlating unique poly-ubiquitin signatures with disease progression.
Currently there is no blood-based test for diagnosis of Parkinson’s disease. Application of this test for late onset PD diagnosis includes up to one million patients in the USA alone. Connect with our R&D team in Malvern, PA to discuss collaborative trials or assay access.
