Geon 15. The Role of Parkin in Parkinson's Disease MT


Parkin is a protein encoded by the PARK2 gene. Its mutations lead to early-onset Parkinson's disease (PD). A recent study using induced pluripotent stem cell (iPSC)-derived neurons carrying mutant PARK2 found that the mRNA level of somatostatin (SOM or SST) and the number of SOM-positive interneurons were reduced (Iwasawa et al., 2019). This article will focus on the effects of Parkin on SOM cells and how its mutations may lead to PD.

The Functions of Parkin

Parkin has been demonstrated to promote mitochondrial autophagy (“mitophagy”) (Narendra et al., 2008). Since this discovery, the role of Parkin in PD was predominantly attributed to its ubiquitin ligase function: elimination of impaired mitochondria (Zhang et al., 2016). This prevailing view is now challenged by two recent reports:

  1. The parkin-knockout flies exhibit locomotor defects and dopaminergic neuron loss resembling PD, but the basal mitophagy is not significantly affected (Lee et al., 2018).
  2. Hundreds of naturally occurring Parkin variants have been reported, but only a minority of Parkin variants, even among those previously associated with PD, disrupted the ligase function of Parkin (Yi et al., 2019).

Parkin has also been demonstrated to stabilize microtubules (Yang et al., 2005; Ren et al., 2009; Ren et al., 2015), which play a crucial role in Intracellular transport. Dysfunction of microtubules may impair axonal transport of essential cellular components such as mitochondria, eventually leading to loss of affected neurons. In PARK2 knockout mice, changes of microtubule stability was found to precede the alteration of mitochondria transport (Cartelli et al., 2018).

SOM Cells and Beta Oscillations

The somatostatin (SOM or SST)-positive cells are a class of inhibitory GABAergic interneurons commonly used to mediate local synchronization (Chapter 7). SOM cells fire at 10-30 Hz with low threshold, thus also called low-threshold-spiking (LTS) interneurons (Mancilla et al., 2007). Note that the oscillations of SOM cells cover the entire beta band (13 - 30 Hz). However, SOM cells are not the only source of beta rhythms. A set of pyramidal neurons in layer 5 (L5) of somatosensory and motor cortices were found to generate high beta (20 - 30 Hz) oscillations (Roopun et al., 2006; Yamawaki et al., 2008).

In the subthalamic nucleus (STN) of PD patients, the beta oscillations are exaggerated (Weinberger et al., 2006; Tinkhause et al., 2018). The neurotoxins, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA) and rotenone which are frequently used in animal models for PD, have been shown to induce excessive beta activities (Nambu and Tachibana, 2014; Mallet et al., 2008; von Wrangel et al., 2015). Mutations of Parkin also lead to exaggerated beta synchrony, particularly in the high beta (20 - 30 Hz) (Moll et al., 2015). As mentioned above, the number of SOM cells decreases in iPSC-derived neurons carrying mutant PARK2 (Iwasawa et al., 2019). Therefore, SOM cells could play an important role in the exaggerated beta activity that characterizes PD.

The Subthalamic Circuit

In STN, about 7.5% of the total neuronal population are GABAergic interneurons (Lévesque and Parent, 2005). Their functional roles were largely unexplored. Since SOM cells oscillate mostly in the beta band, they could be the major GABAergic interneurons in STN, responsible for local synchronization of the projection neurons in STN. On the other hand, STN has direct connection with the motor-related cortical areas via hyperdirect pathway (Nambu et al., 2002). Typically, the cerebral cortex sends output to subcortical areas via layer 5 (L5) pyramidal neurins. Therefore, it is reasonable to assume that the hyperdirect pathway is a direct connection between the projection neurons of STN and the cortical L5 pyramidal neurons that generate high beta oscillations (Roopun et al., 2006; Yamawaki et al., 2008) (Figure 1).


Figure 1. A model for the microcircuit involved in the exaggerated beta activity that characterizes Parkinson's disease. In the subthalamic nucleus (STN), projection neurons (PN) are synchronized by somatostatin-positive GABAergic interneurons (SOM). PN receives direct inputs from layer 5 pyramidal neurons that generate high beta oscillations (20 - 30 Hz). SOM cells mediate local synchronization of PN at full beta band (13 - 30 Hz). In a healthy brain, the two beta sources could be balanced. In Parkin-mutated brains, loss of SOM cells would weaken local synchronization, in favor of long-range synchronization at high beta.

Based on the microcircuit proposed in Figure 1, the projection neurons of STN are influenced by local SOM cells and cortical L5 pyramidal neurons. The SOM cells generate full beta oscillations while the cortical L5 pyramidal neurons generate only high beta oscillations. As discussed in Chapter 14, high beta could represent the motor state, arising from long-range coupling. The finding of Iwasawa et al. (2019) suggests that Parkin mutations may cause loss of SOM cells, possibly due to dysfunction of microtubule transport. This would weaken SOM cell-mediated local synchronization and increase the activity of STN projection neurons. Consequently, the long-range coupling between STN and the cortex is enhanced, reflected in the exaggerated high beta synchrony (Moll et al., 2015).


Author: Frank Lee
First published: May 13, 2019
Last updated: August 26, 2019