Abstract
The discovery of rare familial monogenic forms of early-onset Parkinson's disease has led to the identification of a mitochondrial quality control process as a key player in this disease. Loss-of-function mutations in the genes encoding PINK1 or Parkin result in insufficient removal of dysfunctional mitochondria through autophagy, a process termed mitophagy. Understanding the mechanism of this process and the function of its two key players, PINK1 and Parkin, has led to the discovery of new therapeutic approaches. Small molecule activators of mitophagy, either activating PINK1 or Parkin directly or inhibiting Parkin's counterplayer, the ubiquitin-specific protease USP30, are in preclinical development. To enable clinical success of future small molecule mitophagy enhancers, biomarkers for mitochondrial integrity and mitophagy are being developed. Only a few years after the discovery of mitophagy deficits in Parkinson's disease, research of the underlying mechanisms, drug discovery of modulators for this mechanism and identification of biomarkers provide new avenues towards the development of disease-modifying therapies.
Original language | English |
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Pages (from-to) | 7-13 |
Number of pages | 7 |
Journal | Neuroscience Letters |
Volume | 705 |
Early online date | 14 Apr 2019 |
DOIs | |
Publication status | Published - 13 Jul 2019 |
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Keywords
- Parkinson's disease
- Mitophagy
- PINK1
- Parkin
- USP30
- Small molecule
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Therapeutic approaches to enhance PINK1/Parkin mediated mitophagy for the treatment of Parkinson's disease. / Miller, Silke (Lead / Corresponding author); Muqit, Miratul M. K.
In: Neuroscience Letters, Vol. 705, 13.07.2019, p. 7-13.Research output: Contribution to journal › Review article
TY - JOUR
T1 - Therapeutic approaches to enhance PINK1/Parkin mediated mitophagy for the treatment of Parkinson's disease
AU - Miller, Silke
AU - Muqit, Miratul M. K.
N1 - Funding: Wellcome Trust (210753/Z/18/Z), MRC, Parkinson’s UK, Michael J Fox Foundation, J Macdonald MenziesCharitable Trust, BBSRC, Rosetrees Trust and the EMBO-YIP program.
PY - 2019/7/13
Y1 - 2019/7/13
N2 - The discovery of rare familial monogenic forms of early-onset Parkinson's disease has led to the identification of a mitochondrial quality control process as a key player in this disease. Loss-of-function mutations in the genes encoding PINK1 or Parkin result in insufficient removal of dysfunctional mitochondria through autophagy, a process termed mitophagy. Understanding the mechanism of this process and the function of its two key players, PINK1 and Parkin, has led to the discovery of new therapeutic approaches. Small molecule activators of mitophagy, either activating PINK1 or Parkin directly or inhibiting Parkin's counterplayer, the ubiquitin-specific protease USP30, are in preclinical development. To enable clinical success of future small molecule mitophagy enhancers, biomarkers for mitochondrial integrity and mitophagy are being developed. Only a few years after the discovery of mitophagy deficits in Parkinson's disease, research of the underlying mechanisms, drug discovery of modulators for this mechanism and identification of biomarkers provide new avenues towards the development of disease-modifying therapies.
AB - The discovery of rare familial monogenic forms of early-onset Parkinson's disease has led to the identification of a mitochondrial quality control process as a key player in this disease. Loss-of-function mutations in the genes encoding PINK1 or Parkin result in insufficient removal of dysfunctional mitochondria through autophagy, a process termed mitophagy. Understanding the mechanism of this process and the function of its two key players, PINK1 and Parkin, has led to the discovery of new therapeutic approaches. Small molecule activators of mitophagy, either activating PINK1 or Parkin directly or inhibiting Parkin's counterplayer, the ubiquitin-specific protease USP30, are in preclinical development. To enable clinical success of future small molecule mitophagy enhancers, biomarkers for mitochondrial integrity and mitophagy are being developed. Only a few years after the discovery of mitophagy deficits in Parkinson's disease, research of the underlying mechanisms, drug discovery of modulators for this mechanism and identification of biomarkers provide new avenues towards the development of disease-modifying therapies.
KW - Parkinson's disease
KW - Mitophagy
KW - PINK1
KW - Parkin
KW - USP30
KW - Small molecule
U2 - 10.1016/j.neulet.2019.04.029
DO - 10.1016/j.neulet.2019.04.029
M3 - Review article
C2 - 30995519
VL - 705
SP - 7
EP - 13
JO - Neuroscience Letters
JF - Neuroscience Letters
SN - 0304-3940
ER -