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.

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.  

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: 

1. SM Kulich & CT Chu. (2001) Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: Implications for Parkinson's disease.  J Neurochem  77: 1058-1066.
2. JH Zhu, SM Kulich, TD Oury & CT Chu. (2002) Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am J Pathol  161: 2087-2098. 
3. JH Zhu, F Guo, J Shelburne, S Watkins & CT Chu. (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol, 13: 473-481. 
4. JH Zhu, C Horbinski, F Guo, S Watkins, Y Uchiyama & CT Chu (2007). Regulation of autophagy by extracellular signal regulated protein kinases during 1-methyl-4-phenylpyridinium injury.  Am J. Pathol, 170: 75-86. 
5. SM Kulich, C Horbinski, M Patel & CT Chu. (2007) 6-Hydroxydopamine induces mitochondrial ERK activation. Free Rad Biol Med. 43: 372-383. 
6. ED Plowey, SJ Cherra III, Y-J Liu & CT Chu (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells.  J Neurochem 105: 1048-1056. 
7. RK Dagda, J Zhu, SM Kulich & CT Chu. (2008) Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress.  Autophagy, 4: 770-782. 
8. J Zhu, A Gusdon, H Cimen, B Van Houten, E Koc & CT Chu. (2012) Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity. Cell Death Dis 3: e312. doi: 10.1038/cddis.2012.46. 

• Review Articles

1. CT Chu, DJ Levinthal, SM Kulich, EM Chalovich, and DB DeFranco (2004) Oxidative neuronal injury: The dark side of ERK 1/2. Eur J Biochem, 271: 2060-2066. 
2. J Zhu, KZQ Wang & CT Chu. (2013) After the banquet: Mitochondrial biogenesis, mitophagy and cell survival. Autophagy 9: 1663-76.
3. M Verma, EK Steer & CT Chu. (2013) ERKed by LRRK2: A cell biological perspective on hereditary and sporadic Parkinson’s disease. Biochim Biophys Acta (Molecular Basis of Disease)  In press.  

The lecture, SOS: Mitochondrial Distress Signals in Parkinson's Disease, was preceded by the awarding of a bronze medallion by Dean Levine.  A celebratory dinner banquet at the Monterey Bay  Fish Grotto was attended by multiple members of the Martinez family, members of the Oury-Chu family and lab groups, and colleagues in Pathology, Neuropathology and Neurosurgery.

Ruben's paper on non-mitochondrial functions of PINK1 is now out in Journal of Neurochemistry.

Key findings include the concept that PINK1 does not just sense dysfunctional mitochondria, but is released from  healthy mitochondrial as a signal to promote dendritic growth and differentiation.

http://onlinelibrary.wiley.com/doi/10.1111/jnc.12494/full