Hallmark of Neurodegeneration

The ubiquitin proteasome system (UPS) is the guardian of the cell. It removes damaged proteins and organelles and keeps the intracellular protein traffic running smoothly. In both Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) the accumulation of protein aggregates, such as α-synuclein and tau aggregates depolarize mitochondria. Dysfunctional mitochondria and loss of ATP is the main cause of neuronal cell death. We believe that dysfunction in the UPS is the root cause of neurodegeneration. Novel and groundbreaking therapeutics are emerging by targeting the UPS. LifeSensors is at the forefront of neurodegeneration research and the discovery of neuronal biomarkers.

Understanding Parkinson’s Disease

Parkinson’s Disease (PD) is a progressive neurological disorder that affects movement. Over time, individuals may have trouble with balance, walking, and coordination. Parkinson’s Disease can also affect non-motor functions, leading to cognitive and behavioral changes. Research shows that mitochondrial dysfunction plays a significant role in Parkinson’s Disease (PD) progression. Impaired mitochondria lead to increased oxidative stress, reduced ATP production, and neuronal damage, particularly in dopamine-producing neurons. Targeting mitochondrial dysfunction is a promising approach for developing therapies to slow or halt PD progression.

PINK1 & Parkin: Key Players in Neuronal Health

Mutations in Parkin (an E3 ubiquitin ligase) and PINK1 (PTEN-induced kinase 1) are associated with early-onset forms of the disease. Parkin functions as an E3 ubiquitin ligase, tagging damaged or unwanted proteins for degradation by the proteasome. PINK1, on the other hand, plays a role in mitochondrial quality control and the maintenance of cellular homeostasis. Dysfunctional Parkin and PINK1 pathways contribute to mitochondrial dysfunction and oxidative stress, key factors in Parkinson’s pathology.

The Mechanism

When mitochondria are damaged, PINK1, a mitochondrial kinase, is stabilized to generate phospho-ubiquitin. Phospho-ubiquitin binds to Parkin, activating the cytosolic E3 ligase. Activated Parkin builds phospho-poly-ubiquitin chains to induce autophagy, mitophagy, and mitobiogenesis. Mitochondria exploits the UPS and Parkin to repair the damage. Mutations in PINK1 and Parkin lead to neurodegeneration. A remarkable series of experiments demonstrate that mitochondria conspire to recruit the UPS by phosphorylating ubiquitin by PINK1 kinase and jumpstarting Parkin ligase. Nature is elegant, the UPS needs ATP to function, and mitochondria needs the UPS to repair itself and prevent neurodegeneration.

LifeSensors Offers Assays and Reagents for Neuroscience

  • PROTAC approaches for Tauopathies and α-synucleinopathies
  • Research services on E3 ubiquitin ligases 
  • Biomarker development for Parkinson’s disease / Alzheimer’s disease
  • PD research products

LifeSensors is Leading the Search for Biomarkers

Phospho-ubiquitin is an alarm bell and a biomarker for neurodegeneration. LifeSensors has developed high affinity tools to enrich phospho-ubiquitin and phospho-Parkin from brain tissue, CSF, and serum. These tools can be applied for developing ultra sensitive assays for biomarker development and diagnostic applications. Lifesensors has developed unique HTS (High-Throughput System) assays for discovering Parkin modulators. Lifesensors is also developing novel biomarkers for PD and AD.