BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Talks.cam//talks.cam.ac.uk//
X-WR-CALNAME:Talks.cam
BEGIN:VEVENT
SUMMARY:How PINK1- and Parkin-mediated Mitophagy Prevents Neurodegeneratio
 n - Dr Richard J. Youle | National Institute of Neurological Disorders and
  Stroke 
DTSTART:20191002T140000Z
DTEND:20191002T150000Z
UID:TALK120415@talks.cam.ac.uk
CONTACT:Hannah Burns
DESCRIPTION: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 specifi
 cally on the outer membrane of damaged mitochondria where it phosphorylate
 s ubiquitin chains. These phosphorylated ubiquitin chains on the outer mit
 ochondrial membrane bind to cytosolic Parkin and activate Parkin’s E3 ub
 iquitin 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 additi
 on to NDP52. Optineurin and NDP52 bind to ubiquitin chains on mitochondria
  and also recruit autophagy machinery proteins\, including the upstream ki
 nase Ulk1 and the downstream autophagosome marker\, LC3\, to induce engulf
 ment of the damaged mitochondria. Interestingly\, in a murine model of mit
 ochondrial damage\, the product of the kinase PINK1 (phospho-S65 ubiquitin
 ) is detected to increase in the cortex\, representing a biomarker of PINK
 1 activity. Although mutations in Parkin and PINK1 in man lead to PD\, mic
 e lacking either or both genes have no PD related phenotypes. However\, if
  mice are stressed\, either by the exacerbation of mitochondria DNA mutati
 on rates or by exercise\, profound inflammatory phenotypes arise\, several
  of which are linked to human PD patients. The inflammation appears to ste
 m from mitochondrial DNA released into the cytosol when mitophagy does not
  clean up damaged mitochondria. Interestingly\, preventing inflammation th
 rough the cGAS/STING pathway prevents neurodegeneration in a mouse model a
 nd suggests pharmaceutical treatment could potentially mitigate neurodegen
 eration.\n
LOCATION:Sackler Lecture Theatre (Level 7) The Keith Peters Building\, Cam
 bridge Biomedical Campus
END:VEVENT
END:VCALENDAR