Mutations in the PINK1 and parkin genes lead to mitochondrial dysfunction and the onset of Parkinson's disease. PINK1 and parkin help maintain mitochondrial integrity and function by promoting mitophagy, the degradation of damaged mitochondria. Mutations in these genes impair this process. Specifically, dysfunctional PINK1 fails to properly regulate mitochondrial turnover. Mutations in parkin inhibit its localization to mitochondria and reduce its E3 ubiquitin ligase activity, preventing damaged mitochondria from being tagged for autophagy. This mitochondrial dysfunction, along with increased oxidative stress and reduced ATP production, leads to neurodegeneration in the substantia nigra, the characteristic pathology of Parkinson's disease.

1. The Role of PINK1 and Parkin in the Onset of
Parkinson’s Disease
Ryan Elido
Biology Department, Pacific University, Forest Grove, OR
Background
Parkinson’s disease is the second most common type of
neurodegenerative disorder in humans (Chen & Chan, 2009).
According to the Parkinson’s Disease Foundation website, it is
estimated that seven to ten million people worldwide are living with
Parkinson’s disease. Most individuals are diagnosed with Parkinson’s
at the age of 60 years old. Parkinson’s is characterized by tremors of
the limbs while resting, “cogwheel” movement in limbs, a slow and
disturbed gait, and muscle weakness in the face and throat.
Degeneration of dopaminergic neurons in the substantia nigra was
seen in post-mortem autopsies in people who died with Parkinson’s
(Chen & Chan, 2009; Gispert et al., 2009; Chaturvedi & Beal, 2013;
Janezic et al., 2013). The substantia nigra is a structure located in the
mesencephalon of the brain and is associated with the reward
pathway and movement. It is characterized by a dark stripe due to a
high concentration of neuromelanin in this region and primarily
contains dopaminergic neurons. While the causes of the majority of
Parkinson’s cases are idiopathic or unknown, about 10% of cases are
familial and linked to defective genes (Chen & Chan, 2009).
Treatment options are limited to physical and occupational therapy
and therapeutic drugs designed to alleviate the symptoms
associated with Parkinson’s. Mitochondria are organelles that are
responsible for many cellular functions such as producing energy-rich
molecules (ATP and NAD+) and apoptosis. Both PTEN induced
putative kinase 1 (PINK1) and parkin are involved in maintaining
mitochondrial integrity and degradation (mitophagy) (Chaturvedi &
Beal, 2013; Gispert et al., 2009; Chen & Chan, 2009). A decrease in
the mitochondrial membrane potential (ΔΨm) results in the inhibition
of PINK1 degradation, therefore causing an accumulation of PINK1
proteins (Fedorowicz et al., 2013; Jones, 2010).
Evidence Conclusions
Evidence suggests that removing the PINK1 gene affects the
regulation of mitochondrial turnover and degradation. Parkin also
plays an important role in maintaining mitochondrial integrity, which is
evident in the findings of Clark et al. (2006). In addition, parkin is
shown to be involved in mitochondrial localization and PINK1 activity
(Koyano et al., 2013). PINK1 acts upstream from parkin, meaning that
these two genes are located in the same biochemical pathway.
Mutations in either PINK1 or parkin lead to the decrease in
mitochondrial activity, increased levels of ROS, and decreased levels
of antioxidants like glutathione. This series of events is what is thought
to lead to neurodegeneration and the cause of Parkinson’s disease.
New questions that have developed include: Is there a connection
between idiopathic and familial forms of Parkinson’s? Are there other
genes involved in the onset of Parkinson’s disease? Future directions
to this analysis include the use of human dopaminergic neurons to
study the effects of PINK1/parkin mutations.
Literature Cited
Anichtchik, O., Diekmann, H., Fleming, A., Roach, A., Goldsmith, P., and Rubinsztein, D. C. “Loss of PINK1 Function Affects Development and
results in Neurodegeneration in Zebrafish.” J. Neurosci. 28.33 (2008): 8199-8207.
Chaturvedi, R., and Beal, M. "Mitochondrial Diseases of the Brain." Free Radical Biology and Medicine. (2013): 2-9.
Chen , H., and Chan, D. "Mitochondrial dynamics - fusion, fission, movement, and mitophagy - in neurodegenerative diseases." Human Molecular
Genetics. 18.2 (2009): 169-176.
Clark, I. E., Dodson, M. W., Jiang, C., Cao, J., Huh, J. R., Hong Seol, J., Ji Yoo, S., Hay, B. A., and Guo, M. “Drosophila PINK1 is Required for
Mitochondrial Function and Interacts Genetically with Parkin.” Nature. 441. (2006): 1162-1166.
Fedorowicz, M.A., de Vries-Schneider, R., Rüb, C., Becker, D., Huang, Y., Zhou, C., Wolken, D., Voos, W., Liu, Y., and Przedborski, S. “Cytosolic
Cleaved PINK1 represses Parkin Translocation to Mitochondria and Mitophagy.” EMBO Reports. 15.1 (2013): 86-93
Gispert, S., Ricciardi F., et al. "Parkinson Phenotype in Aged PINK1-Deficient Mice is Accompanied by Progressive Mitochondrial Dysfunction in
Absence of Neurodegeneration." PLoS ONE. 4.6 (2009): 1-15.
Janezic, S., Threlfell S., et al. "Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model." PNAS.
(2013): 1-10.
Jones, R. “The Roles of PINK1 and Parkin in Parkinson’s Disease.” PLoS Biol. 8.1 (2010): 1-2.
Koyano, F., Okatsu, K., Ishigaki, S., Fujioka, Y., Kimura, M., Sobue, G., Tanaka, K., and Matsuda, N. “The principal PINK1 and Parkin cellular
events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons.” Genes to Cells. 18 (2013):
672-681.
Parkinson's Disease Foundation (PDF). n.p., n.d. Web. 20 Apr. 2014. <http://www.pdf.org>.
Trancikova, A., Tsika, E., Moore, D. J. “Mitochondrial Dysfunction in Genetic Animal Models of Parkinson’s Disease.” Antioxidants & Redox
Signaling. 16.9 (2012): 896-919.
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Specific Question
How do mutations in PINK1 and parkin affect
mitochondrial function and lead to Parkinson's
disease?
Broader Implications
Parkinson’s disease is the second most common form of
neurodegenerative disorder in humans. Treatment options remain
limited to physical therapy and medication (e.g. L-DOPA). Although
90% of Parkinson's cases are of unknown origins, understanding the
development of familial forms of Parkinson’s can aid in the
development in preventative treatments. The option of gene therapy
is possible if the mechanism of the PINK1/parkin pathway is better
understood. New drugs can be developed to counter the effects of
this mutation and prevent the onset of this disease. In the meantime,
the goal is to prevent the development of this disease by refraining
from drug consumption (e.g. opioids), as well as living a healthy
lifestyle to postpone the development of this disease. Combined
costs for treatments and government assistance can cost up to $25
billion per year in the United States alone (pdf.org). Once new forms
to prevent the onset of this disease have been developed, overall
costs to care for patients with Parkinson’s will decrease, which
benefits the public’s health and our economy.
Figure 2. Survival rates of wild type
versus PINK1 mutant Drosophila after
exposure to different stressors (a-d)
and ATP concentration in muscle (f)
Graph shows a decrease in survival
rates among PINK1 mutant flies after
each treatment. (f) shows an overall
lower concentration of ATP in PINK1
mutants compared to WT flies.
Dysfunctional PINK1 genes decreases
the organism’s resistance towards
oxidative stress and damage due to
the presence of reactive oxygen
species (ROS). According to the data,
PINK1 mutations affect electron
transport chain due to low yield of ATP
in PINK1 mutants (f). Increased
sensitivity to oxidative stress coupled
with a low yield in ATP production can
result in damaged to affected cells
and cell death. (Clark et al., 2006).
Table 1. Mitochondrial dysfunction due to PINK1 and parkin gene knockouts. Missing or non-
functional PINK1 and parkin genes results in a change of mitochondrial activity; a missing parkin
gene results in a decrease in respiration (low ATP production). In addition, missing both PINK1 and
parkin results in a decreased mitochondrial membrane potential, affecting PINK1/parkin pathway,
as well as increased ROS levels and decreased antioxidant levels (i.e. glutathione). (Trancikova et
al., 2013).
Figure 1. Parkin mutations impair mitochondrial localization and E3 activity after
carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment for 3 hours at
30 uM in mouse neurons. (B) Number of neurons with GFP-parkin on
mitochondria. (C)E3 activity of parkin with parkin mutations shown using
immunoblotting with an anti-parkin antibody. With the exception of the R275W
cell line, presence of ubiquitin-GFP-parkin not present in CCCP-treated cells
with mutated parkin. Mutations in parkin affect autophagy of mitochondria due
to the impairment of PINK1/parkin function. Without the degradation of
damaged mitochondria, abnormal cell function can result, leading to the onset
of disease like Parkinson’s (Koyano et al., 2013).
(Chen & Chan, 2009)
(Fedorowicz et al., 2013)