In addition to promoting mitochondrial function and regulating disposal of damaged mitochondria, we discovered that the kinase PINK1 promotes the growth or maintenance of robust and highly branched dendritic arbors. In this study, we discovered that the mechanism involved interactions of PINK1 with valosin-containing protein (VCP), resulting in phosphorylation of the VCP cofactor p47. This represents the first neuron-specialized function reported for this ubiquitously expressed kinase, whose recessive mutations cause Parkinson's disease, neuropsychiatric symptoms and dementia.
We further discovered that PINK1 can phosphorylate and activate PKA, a master regulator of synaptic function and many other cellular functions related to extracellular and calcium signals. We propose that functioning mitochondria release processed and active PINK1, which acts as a signal of mitochondrial health, cooperating with VCP to promote dendritic extension, branching or maintenance. In contrast, depolarized mitochondria are unable to import, process and release PINK1, resulting in recruitment of Parkin and activation of one of the pathways leading to mitochondrial disposal through mitophagy.
Interestingly, mutations in VCP also cause neurodegeneration (frontotemporal dementia) as well as muscle and bone diseases. The convergence of two genes linked to different neurodegenerative diseases suggests that strategies to enhance this pathway may lead to new therapeutic directions.
Read more in eNeuro: https://www.eneuro.org/content/5/6/ENEURO.0466-18.2018
Read the F1000 recommendation at: https://f1000.com/prime/734664398
See also: https://chulab.weebly.com/news/our-fifth-faculty-of-1000-recommended-article
Post-doctoral alumnus Ruben Dagda, who trained in the Chu laboratory from 2006-2012, has informed me that his first R01 has just been funded for 5 years! Ruben continues to collaborate with the lab in studies of PINK1, publishing a study entitled "PINK1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA" last year.
Other lab alums successfully transitioning to independence include:
Craig Horbinski, former post-doc - transitioned from K08 to his first R01 in 2017
Salvatore Cherra III, former graduate student - K99/R00 funded in 2016
Ed Plowey, former PIRRT fellow - received his K08 in 2014.
Autophagy in the limelight. Dr. Yoshinori Ohsumi wins the 2016 Nobel Prize in Physiology or Medicine!
Manish won first place and a cash prize for his molecular, biochemical and live neuron imaging study of mitochondrial calcium dysregulation in the mutant LRRK2 neuron model.
Jason received a $1000 travel award for his exciting discovery that the "Sensitivity of Mitochondrial Respiratory Chain Complex I to Toxin Inhibition is Activity-Dependent in Neurons," from the American Association of Neuropathologists at the annual meeting in Denver, CO.
He was also awarded a $10,000 Pathology Postdoctoral Research Training Program (PPRTP) research grant from "a very competitive group of applications," which will allow him to collect preliminary data on respiratory chain post-translational modifications to support a K99/R00 application.
Ed will be honored by the ASCI, the premier scientific association for physician-scientists, with a $500 award at its annual meeting on April 25! I had nominated him for the 2015 Young Physician-Scientist Award based on his novel discoveries as a recently independent investigator that the autophagy protein beclin1 has additional roles sorting surface amyloid precursor protein for plasma membrane autophagy and endolysosomal degradation. Such work has implications both for our basic understanding of alternative pathways for plasma membrane degradation, and for Alzheimer's disease mechanisms Congratulations, Ed!
Ed just received notification that his K08 application, entitled NMDA receptor trafficking by the autophagy regulatory protein berlin 1 will be funded!
Two of his papers have also recently been accepted -- one on mutant LRRK2 electrophysiology in BBA-Molecular Basis of Disease from his work in our lab, and a new paper from his lab on transcriptional regulation of beclin 1 complexes in Autophagy.
A great Spring - 3 papers accepted in 4 weeks! Part 1 - the balance of mitochondrial biogenesis and mitophagy in PD: Dual roles for ERK1/2
Kent Wang's study of a novel phosphorylation site on the mitochondrial transcription factor TFAM comes full circle from the first Chu Lab research paper by Scott Kulich 13 years ago.
The discovery that ERK1/2 directly phosphorylates TFAM at S177 to selectively interfere with TFAM promoter binding and transcription, while not affecting non-selective mtDNA binding and packaging, explains how chronic complex I inhibition triggers a deficit in regenerative biosynthesis of the mitochondrial respiratory chain.
This answers in part questions posed by the Kulich study and subsequent studies: Why is sustained ERK1/2 activation as seen in the 6-OHDA and MPP+ models of Parkinson disease and in sporadic and mutant LRRK2 Parkinson disease patient brains harmful to neurons? What is mitochondrially activated ERK1/2 doing? Why is mitophagy harmful in certain contexts, such as these three models, but beneficial in other contexts?
The answer appears to be that sustained ERK1/2 activation, driven by mitochondrial oxidative stress or by dominant mutation in LRRK2, concurrently triggers mitochondrial clearance by mitophagy and suppression of mitochondrial biogenesis. Remaining questions include characterization of other ERK1/2 dependent phosphorylation sites, direct study of mitochondrial biogenesis in the LRRK2 model, and identification of specific molecular targets by which ERK1/2 triggers mitophagy.
Read it here: Mitochondrion, 2014, in press. Click on blue words for links to web articles.
Prior lab studies of ERK1/2 in Parkinson Disease:
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