Ongoing Research Projects

Dagda Lab

Ongoing Research Projects

Dagda Lab

1. Persistent dephosphorylation by mitochondrial localized protein phosphatases (protein phosphatase 2A) accelerates neurodegeneration, fragments mitochondria and impairs mitochondrial function. On the other hand, mitochondrial serine/threonine kinases PTEN induced kinase 1 (PINK1) and PKA confer neuroprotection and regulate overlapping mitochondrial functions. Neurons rely on functionally efficient mitochondria to power critical neuronal functions. Given that impaired mitochondrial turnover and dysfunction underlie the etiology of many neurodegenerative diseases, understanding how reversible phosphorylation at the mitochondria regulates mitochondrial function, and turnover will lay the basic groundwork for developing future "mitoprotective" therapies for reversing mitochondrial dysfunction and neurodegeneration. Preliminary data shows that PINK1 and mitochondrial PKA converge at the outer mitochondrial membrane (OMM) to regulate overlapping mitochondrial functions.
The overarching goals of this five year project grant is to investigate the role of PINK1 in:

1) regulating dendrite integrity by regulating PKA signaling in neurons,
2) regulate mitochondrial trafficking in dendrites through D-AKAP1/PKA and,
3) regulate dendritic development by stimulating nuclear PKA and neurotrophic
signaling.
4) regulates mitochondrial turnover (quality control) and ROS production in
Dendrites in the presence and absence of oxidative stress

2. Characterizing the ability of two over-the-counter supplements to reverse clinical
symptoms of Parkinson's Disease: Phase 2"
The objectives of this research project is to determine whether intranasal
formulations of nootropic agents can reverse mitochondrial dysfunction, clinical
symptoms, and neurodegeneration by stimulating BDNF signaling in a rat modesl of
Parkinson's disease and in cultured primary midbrain neurons.

3. "Exploring the toxicity of aggregates associated with protein-misfolding diseases
On this multi-collaborative proposal, we seek to characterize the biochemical and
functional properties of several modifiers of TDP43-mediated toxicity in yeast and
in neuronal cultures using image-based and biochemical approaches. For aim1,
we will identify new and investigate known modifiers of TDP-43 and FUS toxicity.
For aim 2, we will determine if TDP43 can form different conformational variants
(prion-like). For aim 3 will determine how factors that affect prion formation
Influence TDP-43 and FUS aggregation and toxicity. As a supported co-investigator
on the grant, my focus is to translate the findings observed in yeast to neuronal
cell culture models and in primary neurons.

4. "Preclinical and clinical studies of Alzheime'rs disease"
Mitochondrial dysfunction and neurodegeneration in Alzheimer's disease (AD) can be attributed to deregulation of Protein Kinase A (PKA) and neurotrophic signaling. PKA is a well-characterized prosurvival serine/threonine (ser/thr) kinase that modulates mitochondrial function, neuronal survival and differentiation, synaptic plasticity and initiation of prosurvival gene transcription programs. An increase in PKA signaling is associated with elevated mitochondrial function and enhanced dendritic outgrowth in neurons.
The objective of this study is to fill a critical void in the understanding of how disruption PKA and neurotrophic signaling may increase the vulnerability of neurons to the toxic effects of amyloid beta peptide aggregation in the 5X-FAD mouse model of Alzheimer's disease and whether restoring neuroprotective signaling in the mitochondrion reverses neuropathology.

In collaboration with the Lou Ruvo Center for Brain Health in Las Vegas, the second objective is to identify new biomarkers of Alzheimer's disease from fecal matter of Alzheimer's disease patients.