Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons

Leonie M Heger, Rachel M Wise, J Tabitha Hees, Angelika B Harbauer, Lena F Burbulla, Leonie M Heger, Rachel M Wise, J Tabitha Hees, Angelika B Harbauer, Lena F Burbulla

Abstract

Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson's disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients' somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.

Keywords: Parkinson’s disease; dopaminergic neurons; iPSC; mitochondria.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Bioenergetics:GBA1 and Parkin deficiency, with mutant Parkin also being involved in suppression of complex IV proteins. Furthermore, a major bioenergetic burden has been reported in genetic PD neurons with mutations in DJ-1, GBA1, LRRK2, VPS35 and SNCA to result in reduced mitochondrial respiration capacity, or in neurons with mutant LRRK2, VPS35, SNCA and PINK1 to suffer from reduced mitochondrial membrane potential (ΔΨm). Fission/Fusion: The balance of fission and fusion has been shown be disrupted in several iPSC-derived models of genetic PD with mutant PINK1 and Parkin leading to enlarged/elongated organelles, and mutant GBA1 to rather swollen mitochondrial structures. Excessive mitochondrial fragmentation has been demonstrated in mutant Parkin and VPS35 neurons, as well as in neurons from SNCA and LRRK2 patients, a phenotype that is suggested to be associated with increased Drp1 activity in the latter. Axonal transport: Aberrant α-syn expression was shown to interfere with anterograde axonal transport, while mutant LRRK2 leads to enhanced mitochondrial motility in human neurons. Alterations of both proteins have also been shown to be involved in Miro1 kinetics by delaying Miro1’s removal from mitochondria, thereby interfering with proper mitochondrial clearance (mitophagy) under conditions of mitochondrial depolarization. Additionally, destruction of microtubules themselves has been reported in Parkin patient neurons. Mitophagy: PINK1/Parkin-dependent mitophagy has been well characterized, hence, not surprisingly, mutant PINK1 and Parkin patient neurons demonstrate impaired mitophagic flux, partially based on studies reporting reduced levels of phosphorylated ubiquitin (Ser65) and impaired recruitment of Parkin to mitochondria upon mitochondrial depolarization. Both LRRK2 and GBA1 mutations have been shown to interfere with autophagosome (AP) to lysosome transport or mitochondrial-lysosomal colocalization, respectively. Ca2+ handling: Disrupted association between ER and mitochondria for regulation of Ca2+ transfer at MAM sites is a shared phenotype among GBA1, Parkin and SNCA PD mutant neurons, reported to show altered Ca2+ handling. While Parkin mutant neurons show an increased ER-mitochondria association resulting in excessive uptake of Ca2+ into mitochondria, both SNCA triplication neurons and GBA1 mutant neurons suffer from reduced Ca2+ transfer into mitochondria due to (a) interference of α-syn with the ER-associated protein VAPB (SNCA triplication), and (b) reduced levels of neuronal calcium sensor-1 (NCS-1) (GBA1 mutant neurons) that facilitates MAM formation under normal conditions.

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Source: PubMed

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