Mitochondria in the etiology and pathogenesis

of Parkinson's disease

By: Vargha Eslami Amirabadi, Hui En Sally Chen, Jonathan Nhan, Woo Sik Yoon

Oct. 13, 2015

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

Parkinson’s Disease (PD)

• Destruction of dopaminergic neurons in substantia nigra pars compacta (SNc) and striatum

• Lewy bodies

• Unknown cause1. Sporadic (~90%)2. Familial (~10%)

• No available cure for the disease

~90% ~10%

• MPTP

Parkinson’s Disease

Akinesia, Bradykinesia

Resting tremors

Destruction of DA neurons

Why is dopamine so important?

Mood disordersCatalepsy

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

• Amphiphilic heroine analogue• Evidence linking mitochondrial

dysfunction to PD• Extensively used in animal

models

MPTP Mechanism

Przedborski, S and Vila, M., Clinical Neuroscience Research 1, 407-18 (Dec 2001)

PINK1

• PTEN-induced kinase 1• Encoded by PARK6 gene on chromosome 1 • Autosomal recessive • Studies show early onset of PD caused by mutation at PARK6 locus• Detects initial mitochondria dysfunction, then signals Parkin to

eventually remove damaged mitochondria

Parkin

• Encoded by PARK2 gene on chromosome 6• Mutation in Parkin is the most common cause of autosomal-recessive

PD• Parkin is a ubiquitin E3 ligase neuroprotective function• Parkin tags (ubiquinates) damaged mitochondria for mitophagy

Narendra, D.P., and Youle, R.J. Antioxidants & Redox Signalling. 14, 1929-1936. (2011)

Narendra, D.P., and Youle, R.J. Antioxidants & Redox Signalling. 14, 1929-1936. (2011)

Pickrell, A.M., and Youle, R.J. Neuron. 85,257-73 (2015)

Current Drug Therapies

• Dopamine precursors• Levodopa (L-DOPA) in combination with Carbidopa

• Dopamine Agonists• Ex: Pramipexole (Mirapex)

• MAO-B Inhibitors• Ex: Rasagiline (Azilect)

• Catechol-O-methyltransferase (COMT) inhibitors• Ex: Entacapone (Comptan®)

• Anticholinergics• EX: Benztropine (Cogentin)

Dopamine synthesis

Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006)

Mitochondria-targeted antioxiadants (MTAs)

• Lipophilic cation allows targeting to mitochondria

P+X

X=Antioxidant moeity

Triphenylphosphonium (TPP)

P+

O

O

O

O

Example: MitoQ10

Summary

• PD caused by destruction of dopaminergic neurons in midbrain (SNc + striatum)• Sporadic (spontaneous/unknown) and familial (genetic) causes, but suggested to be mix of both

factors• MPTP induces acute PD symptoms by ROS and activation of the apoptosis cascade• MPTP linked role of mitochondrial dysfunction to PD• Under normal conditions, PINK1 and parkin dispose of dysfunctional mitochondrial by

ubiquitination leading to autophagy (mitophagy) • Suggested that mutations in either gene lead to dysfunctional control system and survival of

dysfunctional mitochondria = increase ROS and destruction of dopaminergic neurons• PD treatments mostly alleviate motor symptoms without slowing progression• L-DOPA (crosses BBB) with Dopadecarboxylase inhibitors (prevent conversion of L-DOPA to

dopamine) most common and effective treatment• MTA - Lipophillic cation (ie. TPP) + Antioxidant (ie. MitoQ10), being explored as possible therapy

to target mitochondria

References

• Jin, H., Kanthasamy, A., Ghosh , A., Anantharama, V., Kalyanaraman , B., and Kanthasamy, (2014) A.G. Mitochondria-targeted antioxidants for treatment of Parkinson's disease: Preclinical and clinical outcomes. Biochimica et Biophysica Acta. 1284-1294.

• Narendra, D.P., and Youle, R.J. (2011) Targeting Mitochondrial Dysfunction: Role for PINK1 and Parkin in Mitochondrial Quality Control. Antioxidants & Redox Signalling. 14, 1929-1936

• Pickrell, A.M., and Youle, R.J. (2015) The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease. Neuron. 85,257-73

• Przedborski, S., and Miquel, V. (2001) MPTP: a review of its mechanisms of neurotoxicity. Clinical Neuroscience research. 1, 407-18

• Sanchez-Padilla, J., Guzman, J.N., Ilijic, E., Kondapalli, J., Galtieri, D.J., Yang, B., Schieber, S., Oertel, Q., Wokosin, D., Schumacker, P.T., and Surmeier, D.J. (2014) Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. Nature neuroscience. 17, 832-42