By: Derrick Padykula and Isabelle Wentzel
Hallmark of Neurodegeneration
Diving into the complex world of neurodegeneration unveils the long road marked by the gradual decline of neuronal cells, ultimately leading to cell death. In Parkinson’s disease (PD) and Alzheimer’s disease (AD), the accumulation of aggregated proteins and dysfunctional mitochondria is what contributes to the demise of these neuronal cells. The unsung heroes of mitigating neurodegeneration, the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway (ALP), play pivotal roles in neurodegenerative diseases. The promise of neuroprotection and revolutionary therapeutic possibilities for PD and AD lies in the directed breakdown of these aggregated proteins and impaired mitochondria (1).
Master Regulators: PINK1 and Parkin
Meet the masters behind mitochondrial health – the E3 ligase Parkin and PTEN-induced kinase 1 (PINK1). Mitochondria are responsible for more than 90% of your body’s energy production. PINK1 and Parkin not only keep your energy flowing, but also coordinate other various cellular physiological processes, like cell fate, differentiation, proliferation, and apoptosis (2). Mitochondrial dysfunction and stress, whether induced by environmental factors, pathogenesis, or aging, results in a range of dysregulations that can contribute to both neurodegeneration and neuroinflammation (3).
When mitochondria become damaged and depolarized , PINK1 will accumulate on the outer mitochondrial membrane. This event will recruit Parkin to the membrane, where PINK1 will phosphorylate both ubiquitin and Parkin. Binding of phospho-ubiquitin to phospho-Parkin allows Parkin to be in its fully active state. Parkin will then ubiquitinate mitochondrial membrane proteins, initiating the process of mitophagy and clearance of damaged mitochondria.
Search for a Biomarker
Mutations in Parkin, PINK1, and other related proteins can predispose individuals to PD. Researching these processes in relation to the UPS remains an important feat to unlock the secrets of PD. LifeSensors emerges as a beacon in the field of neurodegeneration research, offering several tools, innovative technologies, and knowledge solutions for advancing research in the field of neurodegeneration. Among these, TUBEs (Tandem Ubiquitin-Binding Entities) stand out, exhibiting high nanomolar binding affinities to ubiquitin chains. LifeSensors offers both chain-selective and pan-selective TUBEs, providing researchers with unparalleled versatility. The comprehensive study of ubiquitinated proteins and the entire ubiquitome becomes possible with pan-selective TUBEs like TUBE1 and TUBE2.
A Comprehensive Approach to Challenging Research Areas
In the realm of neurodegenerative diseases affecting the central nervous system (CNS), LifeSensors offers a comprehensive suite of services to unravel the intricacies of disease pathophysiology and facilitate therapeutic advancements. LifeSensors recognizes the challenges posed by poorly understood mechanisms and complex disease pathways, and its Proteolytic Targeted Chimera (PROTAC®) protein degraders represent a groundbreaking approach. These innovative PROTACs demonstrate improved pharmacology to breach the blood-brain barrier, heightened catalytic activity to break down aggregates, and adaptability to various delivery mechanisms. The emphasis on studying novel E3 ligases compared to traditional counterparts highlights LifeSensors’ commitment to generating polyubiquitin chains for both proteasomal and lysosomal degradation. LifeSensors’ services extend to in vitro Tau aggregation models, ubiquitination assays targeting protein aggregates, ubiquitin chain-selective TUBEs for high-throughput screening, and mass spectrometry ubiquiteomics. With a focus on advancing mechanistic insights, LifeSensors’ custom high-throughput assays contribute to the design of reliable Structure-Activity Relationships (SARs) and foster progress in neurodegenerative disease research. Additionally, our range of related products, including TUBEs, E3 Ubiquitin Ligases, and Mass Spectrometry Ubiquiteomics, showcases a commitment to cutting-edge technologies in the pursuit of understanding and treating these challenging conditions.
In essence, the hallmarks of neurodegeneration emphasize the pivotal role played by LifeSensors in spearheading advancements for understanding and treating complex neurodegenerative diseases. With a commitment to innovation and cutting-edge solutions, LifeSensors paves the way for a future where effective treatments for these challenging conditions are within reach.
References
- Pickrell, A. M. & Youle, R. J. The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson’s Disease. Neuron 85, 257–273 (2015).
- Javadov, S., Kozlov, A. V. & Camara, A. K. S. Mitochondria in Health and Diseases. Cells 9, 1177 (2020).
- Ge, P., Dawson, V. L. & Dawson, T. M. PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease. Molecular Neurodegeneration 15, 20 (2020).