The Role of Parkin in Parkinson’s Disease
How Amino Acid Homeostasis is Impacted by Mitochondria-Lysosome Contact Sites
Background
Parkinson’s Disease (PD) is a neurodegenerative disorder of the central nervous system characterized by uncontrollable muscle spasms or stiffness and shaking known as tremors. Parkinson’s is the second most common neurodegenerative disorder. It is a chronic disease, meaning it is not curable, so treatments focus on managing symptoms and slowing disease progression. Symptoms can include tremors and uncontrollable spasms (this involuntary movement is called dyskinesia), muscle stiffness, impaired coordination and balance, and limited voluntary muscle control, which can impact things like speaking or chewing.
PD is caused by deficiencies in the neurotransmitter dopamine, which is responsible for cell signaling in neurons along with other important functions within the body. Dopamine deficiency is detrimental to the whole body and can come about in several ways. In general, this loss of dopamine occurs because neurons within the basal ganglia (the substantia nigra pars compacta: a part of the brain responsible for movement) die, or their ability to produce dopamine becomes impaired. Decreased dopamine production results in the dyskinesia symptoms most associated with the disease.
Summary
There are multiple kinds of Parkinson’s disease, and they are characterized by when symptoms present themselves and what genes are affected. This paper focuses on mutations of PARK2, which is the most common genetic cause of early-onset (approximately 31 years at age of onset) Parkinson’s Disease. Early-onset Parkinson’s Disease is caused by PARK2 mutations, which impact the efficacy of the E3 ubiquitin ligase parkin. Ubiquitin ligases are responsible for tagging structures in the cell for destruction, and their impairment can play a major factor in disease through product buildup within the cell, or broken structures not being degraded.
This paper studied the role of parkin in organelle tethering (organelle communication) between the mitochondria and the lysosome. These organelles communicate through points of contact regulated by proteins called Rab7, which tethers mitochondria and lysosome together for effective contact, and Rab7 GAP. GAP proteins are responsible for removing a phosphate group from the GTP that activates the Rab7 protein, and removing this phosphate group inactivates the Rab7 protein. The researchers used dopaminergic (dopamine releasing) neurons to study these contact points and found that in the parkin PD neurons the contacts between the mitochondria and lysosome were reduced.
First, the researchers used transcriptomics (measurements of transcribed RNA proteins) and metabolomics (measurements of substrates and biproducts from metabolism) to look at the gene pathway. These tests found that gene transcriptions were regulated differently, and this was associated with disrupted amino acid metabolism pathways. These disrupted pathways impacted amino acid homeostasis, and this led to the whole cell having amino acid deficiencies in the parkin PD neurons.
After finding the whole cell amino acid deficiency results, the researchers looked at how this changed amino acid homeostasis might interact with the mitochondria and lysosome, which are both organelles heavily involved with amino acids. They did this by testing two different kinds of parkin genes, the wild type (normal, not modified parkin gene coding for functional ubiquitin ligases), and a mutant gene coding for a non-functional ubiquitin ligase. The wild type neuron displayed normal mitochondria-lysosome contacts, while the mutant gene did not have normal contacts, and this data suggests that functional ubiquitin is required for stable mitochondria-lysosome contacts.
Mitochondria-lysosome contacts are also regulated by another protein called Rab7, which encourages stable tethering when active and working. Parkin can inactive Rab7 by using a Rab7 GAP, which removes the activating phosphate group and turns the Rab protein off. Rab7 being turned off results in contact destabilization in parkin PD neurons, but turning Rab7 back on by blocking the Rab GAP can restore stable contacts. Restoring these contacts between organelles can help the cell to restore amino acid homeostasis by keeping the amino acids that should be in the mitochondria within the mitochondria, and the amino acids that should be in the lysosome within the lysosome.
This research shows why it can be so complicated to treat Parkinson’s, because of the complicated interplay between genes and environment, but offers a potential option for therapeutic treatments that could counteract the metabolic problems arising from disjointed organelle contact. More research is needed to further our knowledge of the pathways and contacts and different levels of homeostasis involved in this disease.
