CNS diseases

Literature highlights

Mitochondria provide an essential role in the maintenance of cellular homeostasis with regard to energy generation, redox signaling, and programmed cell death. Consequently, fast adaptation to metabolic changes associated with developmental demands or stress induction requires a balanced coordination of mitochondrial biogenesis and removal of damaged mitochondria. Impaired mitochondrial maintenance is causally linked to many human pathologies and aging, including diabetes, cancer, and neurodegenerative diseases.1 In fact, neurons contain increased mitochondrial population, since high ATP levels are demanded to carry out their functions and preserve neuronal homeostasis.2

Because of the unique neuronal architecture, which is characterized by a relatively small cell body, long axons, and multiple dendritic branches, neurons are equipped with specialized mechanisms for efficient distribution of mitochondria to distal regions, such as presynaptic endings, postsynaptic densities, axonal branches and growth cones, where high energy is required to sustain neuronal activity.3 Post-mitotic neuronal cells must survive during the lifetime of the organism and they are more vulnerable to the process of ageing due to their intensive metabolism and increased ROS generation. Therefore, neuronal activity and survival depend on mitochondrial homeostasis. Dysfunctional mitochondria not only produce less ATP but also display impaired buffering of cytosolic calcium.

Furthermore, elevated ROS production can trigger neuronal stress and lead to neurodegeneration.2 Thus, aged or damaged mitochondria need either to be repaired through mitochondrial quality control mechanisms such as proteasome system, mitochondrial proteases and fission–fusion machinery, or eliminated by mitophagy.

It is therefore of fundamental importance to understand cellular surveillance mechanisms that support a healthy mitochondrial network when focusing on CNS diseases.

1. Franz A., Kevei E., and Hoppe T. Double-edged alliance: mitochondrial surveillance by the UPS and autophagy. Current Opinion in Cell Biology. 2015; 37: 18–27.

2. Rugarli E. I., Langer T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 2012; 31: 1336–1349.

3. Sheng Z. H. Mitochondrial trafficking and anchoring in neurons: new insight and implications. J. Cell Biol. 2014; 204: 1087–1098.

All our assays are fully customizable and can be adapted to meet your specific needs. Contact us to learn how our technologies might be of value to you!

Which technologies to use

Mitoselect

Mitoselect is a technological platform in which patient-derived cell models are developed to test disease modification with the measurement of specific signatures using mitochondrial behavior. Models available include signatures for AD, HD, Parkinson, and LRKK2 Parkinsonnism.

This technology enables you to select disease-modifying drugs for CNS diseases, and qualify and quantify drug activity. You can also partner with us to identify disease signature in pilot cohorts of patients suffering from neuro-degenerative diseases compared to age– and gender-matched controls, or to to identify drug response elements using our proprietary models.

Mitoselect is the simultaneous measure of phenotypes along four dimensions:

  • Motility
  • Morphology
  • Mitochondrial reticular network organization
  • Mitochondrial membrane permeability
mtDNA content and quality control

Abnormal levels of mtDNA have been found in people with abnormal brain MRIs, hypotonia, developmental delays, seizures, or failure to thrive. Hence, we offer a fully quantitative High Content Analysis (HCA) reading of mtDNA content.

mtDNA quality control (mytophagy and fusion/fission dynamics) can also be assessed upon request.

BBS or BBS + package

ICDD's Bioenergetic Balance Screen ((BBS/BBS+) helps you get a finer understanding of your drug's mechanism of action at the mitochondrial level, and evaluate your compound's impact on β-oxidation, oxidative phosphorylation (OXPHOS) and the tricarboxylic (TCA) cycle.

The BBS/BBS+ packages are the multiplexed and integrated measurements, in a same cell, of:

  • Oxygen consumption
  • ATP production
  • Glycolysis level
  • Cell viability
  • TCA cycle turning (BBS+ only)

The BBS package is available in HTS/single point or dose response studies.

Redox status

Our Redox balance, avalaible in HTS/dose response studies, is the measurement of (any or all):

  • ROS mitochondrial production
  • Cytoplasm ROS accumulation
  • MnSOD Cu/ZnSOD activities
  • Catalase activity
  • Total GSH activity
  • Lipid peroxidation level (TBARS)
  • Protein carbonylation
  • Cell viability