Speakers

Richard Youle, PhD

Surgical Neurology Branch, NINDS, NIH, Bethesda, MD USA.

Short Biography

Dr. Youle received an A.B. degree from Albion College and his Ph.D. degree from the University of South Carolina where he worked on the protein toxin ricin. He joined the lab of David Neville at the National Institute of Mental Health for postdoctoral work on the engineering of new cell-type-specific protein toxins. He joined the Surgical Neurology Branch of NINDS in 1985 as a principal investigator. His broad research interests have spanned from basic cell biology pathway identification through the development of targeted therapeutics to brain tumor clinical trials. Insights from his basic research illuminate disease etiology and have led to novel treatment strategies. Over the past decade he has concentrated on the role mitochondria play in apoptosis and the mechanism of mitochondrial turnover and autophagy. Most recently his group has uncovered molecular and cellular roles of two gene products mutated in two forms of inherited Parkinson’s disease, PINK1 and Parkin. PINK1 was found by Youle’s group to selectively flag damaged mitochondria by phosphorylating ubiquitin attached to outer mitochondrial membranes. Phospho-ubiquitin serves as a receptor and allosteric activator of Parkin’s ubiquitin ligase activity that induces further ubiquitination of outer mitochondrial membrane proteins. These phospho-ubiquitin posttranslational products, formed specifically on damaged mitochondria denoted by PINK1, initiate autophagy of the damaged mitochondria. Working together PINK1 and Parkin eliminate damaged mitochondria that may otherwise activate innate immune pathways. Understanding previously unknown molecular mechanisms of mitochondrial quality control guides his current efforts to develop new treatment strategies for mitochondrial and neurodegenerative diseases.

Abstract

Penetrance of inflammation with Parkin and PINK1 mutant gene dosage

PINK1 and Parkin, both mutated in familial PD, normally work intimately together to initiate autophagy of impaired mitochondria. When mitochondria are damaged, Pink1 senses the damage and accumulates specifically on the outer membrane of damaged mitochondria where it phosphorylates ubiquitin chains. These phosphorylated ubiquitin chains on the outer mitochondrial membrane bind to cytosolic Parkin and activate Parkin’s E3 ubiquitin ligase activity yielding a feedback amplification loop that leads to autophagy of individual damaged mitochondria. Downstream of Parkin the machinery that mediates autophagosome recognition of damaged mitochondria links this pathway to genes mutated in ALS. Optineurin and the kinase TBK1, both mutated in familial ALS cases, participate in mitophagy in addition to NDP52. Optineurin and NDP52 bind to ubiquitin chains on mitochondria and also recruit autophagy machinery proteins, including the upstream kinase Ulk1 and the downstream autophagosome marker, LC3, to induce engulfment of the damaged mitochondria. Interestingly, in a murine model of mitochondrial damage, the product of the kinase PINK1 (phospho-S65 ubiquitin) is detected to increase in the cortex, representing a biomarker of PINK1 activity. Although mutations in Parkin and PINK1 in man lead to PD, mice lacking either or both genes have no PD related phenotypes. However, if mice are stressed, either by the exacerbation of mitochondria DNA mutation rates or by exercise, profound inflammatory phenotypes arise, several of which are linked to human PD patients. The inflammation appears to stem from mitochondrial DNA released into the cytosol when mitophagy does not clean up damaged mitochondria. Interestingly, preventing inflammation through the cGAS/STING pathway prevents neurodegeneration in a mouse model and suggests pharmaceutical treatment could potentially mitigate neurodegeneration.