I have been fortunate to work with and guide many fantastic people. This includes high school and undergraduate volunteers, graduate and medical students, post-doctoral and post-graduate fellows, and junior to mid-career faculty. Each mentoring experience has greatly enriched by journey as an Educator, Physician and Scientist.

In the talk, I discussed unexpected findings for the PINK1 field of recessive Parkinson's disease, including the fact that knockout mice do not show overt neurodegeneration. This was followed by our published and unpublished data supporting the hypothesis that autophagy/mitophagy upregulation compensates for PINK1 loss in culture and in vivo. The next unexpected finding was that PINK1-deficient neurons are nevertheless fully capable of upregulating compensatory mitophagy, which led to a major basic science discovery of the cardiolipin pathway of mitophagy cargo specification as reported in Nature Cell Biology and Cell Death and Differentiation. To understand neuron-specialized roles for PINK1, we embarked on immunoprecipitation-mass spectrometry studies that led to the discovery the PINK1 plays a crucial role in dendritic arborization, interacting with valosin-containing protein and protein kinase A to phosphorylate p47, published in the open access SFN journal eNeuro. Delving further into mechanisms that regulate PINK1 proteasomal degradation resulted in a pair of studies published in Journal of Biological Chemistry and JCI Insight. Assisted by our IP-MS data and computational modeling, we identified one of the first small molecules capable of protecting not only against cell death, but also dendritic retraction/simplification elicited by acute parkinsonian intoxication.

As trainees often struggle with the ups and downs of science, I wanted to close by offering some advice for getting the most out of this lifelong journey of discovery. Students sometimes feel discouraged when asked to go delve deeper, move faster, convince skeptics, or reanalyze data when potential flaws are pointed out. Yet science is a lifelong quest for learning, discovery and improvement, even for full professors. Remember, busy people wouldn't care to take the time to offer constructive critiques if they did not believe in you.

For those that were unable to attend the webinar, here is the final slide.

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.

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.