Mutations in PTEN-induced kinase 1 (PINK1) are associated with autosomal recessive forms of Parkinson's disease (PD). In the mitochondrion, full-length PINK1 is proteolytically processed to lower molecular weight forms which are exported to the cytosol. While full-length PINK1 has been implicated in regulating mitophagy and mitochondrial function, the understanding of the functional role(s) of endogenous cleaved PINK1 (c- PINK1) in the brain is limited. Our recent research demonstrates a link of c-PINK1 and regulation of mitochondrial trafficking and dendrite outgrowth via PKA. This model is supported by preliminary and published data from our group, showing that loss of PINK1 function in vivo and in vitro impairs PKA-mediated dendrite connectivity and mitochondrial trafficking, but the connections between these two mechanisms are unresolved. The studies proposed will fill a critical void in our understanding of how c-PINK1 regulates PKA signaling to enhance dendrite connectivity and mitochondrial trafficking in PD models.
In Aim 1, the molecular mechanisms by which PINK1 and dendrite-localized PKA protect dendrites from oxidative stress will be elucidated using image-based and molecular biology approaches.
Aim 2 will elucidate the mechanisms by which PINK1 and PKA regulate mitochondrial trafficking in dendrites, and specifically test the hypothesis that PINK1 acts through PKA to increase mitochondrial content by phosphorylating the mitochondrial trafficking adaptor protein Miro2.
Aim 3 will determine the mechanisms by which PINK1/PKA activation modulates neurite outgrowth. This work is expected to have an impact on health and human diseases in three areas. First, characterizing the PINK1-PKA signaling pathway will identify new protective mechanisms by which this novel signaling axis maintains dendrite homeostasis. Second, experiments proposed in Aims 1 and 2 will help us understand how PINK1 activates PKA signaling in mitochondria and dendrites regulate mitochondrial trafficking and protect dendrites from oxidative stress. Third, since dysregulation of PKA signaling, mitochondrial function, neurotrophic signaling, and loss of dendrites are implicated in multiple neurodegenerative diseases, identifying new dendrite-protective mechanisms can lead to new targeted, rational therapies via enhanced protective PKA signaling.
Mutations in PTEN-induced kinase 1 (PINK1) are associated with genetic forms of Parkinson's disease (PD), a neurodegenerative disorder characterized by the progressive loss of midbrain dopamine neurons. In this research project grant, we propose to functionally dissect the molecular mechanisms by which PINK1 activates compartmentalized PKA signaling to protect dendrites against oxidative stress (Aim 1), modulate mitochondrial trafficking and content in dendrites (Aim 2), and stimulate dendritic connectivity and neurotrophic signaling (Aim 3) in the context of neuronal health and Parkinson's disease. Knowledge gained from studying this novel neuroprotective signaling pathway can contribute to development of therapies for PD that can reverse neurodegeneration by enhancing protective PKA signaling.
| Dagda, Ruben K (2018) Role of Mitochondrial Dysfunction in Degenerative Brain Diseases, an Overview. Brain Sci 8: |
