Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Abstract

Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

Neuroenergetic Changes in Patients with X‐Linked Dystonia‐Parkinsonism and Female Carriers

“…7 Enhancing mitochondrial metabolism may be a therapeutic option in the prodromal and manifest phase of PwXDP, but probably also in het-TAF1 to ameliorate the bioenergetic state, protect mitochondria, and potentially mitigate ongoing neurodegeneration. 23 Potential therapeutic strategies could include agents that boost mitochondrial function or reduce oxidative stress, given the central role of mitochondria in cellular energy production and health. 24 Future studies with larger sample sizes and longitudinal follow-ups are needed to confirm and expand our findings.…”

Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders

“…Genetic insights and pathway-based analyses help elucidate mitochondrial dysfunction's complexity in NDs. We refer the reader to a review article illustrating how these approaches help identify potential treatment strate-gies in patients with genetic and non-genetic Parkinson's disease as a neurodegenerative model disease [23]. Although the evolvement and the individual time course of suspected mitochondrial dysfunction in NDs are only poorly understood, mitochondria-targeted therapies can still be considered a viable treatment strategy for many of these disorders [8].…”

Role of Nrf2 in Parkinson’s Disease: Toward New Perspectives

“…Activation of Nrf2 upregulates the transcription of genes related to essential mitochondrial functions and increases the expression of the multifunctional DNA-binding protein mitochondrial transcription factor A (TFAM), which plays a key role in the expression of the mitochondrial genome. Mitochondria-targeted gene therapy is a potentially promising strategy to improve PD (Prasuhn & Brüggemann, 2021), and mitochondrial dysfunction was demonstrated in the PD mouse model.…”