Parkinson's disease: Research into mitochondria and autophagy

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  • Project duration: -
  • Project status: ongoing
  • Funding:
    Provincial P.-L.P. 14. Mobility (Province BZ funding /Project)
  • Institute: Institute for Biomedicine

Dysfunctions of mitochondria and the autophagy-lysosomal pathway (ALP) take part in the pathologic process of Parkinson’s disease (PD) and are induced by most PD-associated mutations. The Microphthalmia-associated Transcription Factor (MiT) family proteins (MITF, TFEB, TFE3, TFEC) are considered master regulators of autophagy and lysosomal biogenesis and their activity is regulated in response to nutrient availability, therefore connecting cellular metabolism with ALP function.

This project aims at shedding light on a potential mechanistic role of the MiT transcription factor pathway in relation to cellular and mitochondrial health in the etiology of PD and seeks to identify novel targets with the capacity to upregulate the MiT pathway and to increase degradation of aggregates and defective organelles, which may serve as therapeutic approach.

Mechanistic studies will determine how the MiT pathway links mitochondria-lysosomal dysfunctions in the disease cascade of PD in response to metabolic and genetic changes. This will be performed in vitro in SH-SY5Y cells and genetically defined human induced pluripotent stem cells (hiPSC)-derived neurons. In vivo insight will be obtained through internal and external collaborations from C. elegans models and PD-relevant mouse models.

High-throughput screens will aim to discover novel regulators of the MiT pathway, possibly independent of the canonical mTOR pathway. An in vitro CRISPR knockout screen, complemented by genetic screens in C. elegans, will elucidate essential and conserved proteins in the MiT activation pathway. Preclinical validation of identified MiT activators to rescue PD-related phenotypic defects will be carried out in advanced cellular models and in vivo models of PD.

Overall, this project will dissect the link between mitochondrial and ALP dysfunctions in PD and aim to exploit regulation of the MiT pathway as pharmacological target against PD and related neurodegenerative diseases.

Progressive mitochondrial DNA damage in Parkinson’s disease induced pluripotent stem cell-derived neurons
Lang M, Gilmozzi V, Pramstaller PP, Pichler I (2023)

Conference: MitoPorto | Porto | 12.5.2023 - 13.5.2023

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Deep mitochondrial genotyping reveals altered mitochondrial quality control mechanisms in advanced cellular models of Parkinson’s disease
Lang M, Gilmozzi V, Pramstaller PP, Pichler I (2023)

Conference: EUROMIT 2023 - International meeting on mitochondrial pathology | Bologna | 11.6.2023 - 15.6.2023

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The mitochondrial genome: properties, quirks, and implications in disease
Lang M (2023)

Conference: Teaching activity within Course in Genomic Technologies at Department of Cellular, Computational and Integrative Biology - CIBIO | Trento | 15.9.2023 - 15.9.2023

Crosstalk Of Organelles In Parkinson‘s Disease: Mitochondrial And Lysosomal Dysfunctions Connecting Disease Biology And Druggable Targets
Lang M (2022)

Conference: Innsbruck Biocenter Seminar Series SS 2022 | Innsbruck; hybrid/online | 4.3.2022 - 24.6.2022

A genome on shaky ground: exploring the impact of mitochondrial DNA integrity on Parkinson's disease by highlighting the use of cybrid models
Lang M, Grünewald A, Pramstaller PP, Hicks AA, Pichler I (2022)
Journal article
Cellular and Molecular Life Sciences

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Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes
Lang M, Pramstaller PP, Pichler I (2022)
Springer Science and Business Media LLC
Journal article
Molecular Neurodegeneration

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Junge Köpfe - Martin Lang
Lang M, Pramstaller PP, Timm D, Lechthaler H, Lechthaler M, Perwanger M (2021)

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Crosstalk between Mitochondrial Dysfunction and Autophagy in Parkinson’s Disease: a Project Outline
Lang M, Pichler I (2021)

Conference: Molecular Neurodegeneration and Therapeutic Approaches | Virtual event | 25.1.2021 - 29.1.2021

Our partners
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    Medical University Innsbruck

  • University of Bologna, Department of Biomedical and NeuroMotor Sciences

  • University of Luxembourg, Luxembourg Centre for Systems Biomedicine

  • Luxembourg Centre of Neuropathology