Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson's Disease.

Flora Guerra,Marco Mitruccio,Consiglia Pacelli,Giulia Girolimetti,Cecilia Bucci,Tiziana Cocco,Anna Ferretta,Giuseppe Gasparre,Raffaella Beli

doi:10.3390/cells8050452

Abstract

Crosstalk between lysosomes and mitochondria plays a central role in Parkinson’s Disease (PD). Lysosomal function may be influenced by mitochondrial quality control, dynamics and/or respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, is not yet understood. Here, we performed live imaging, western blotting analysis, sequencing of mitochondrial DNA (mtDNA) and senescence-associated beta-galactosidase activity assay on primary fibroblasts from a young patient affected by PD, her mother and a healthy control to analyze the occurrence of mtDNA mutations, lysosomal abundance, acidification and function, mitochondrial biogenesis activation and senescence. We showed synergistic alterations in lysosomal functions and mitochondrial biogenesis, likely associated with a mitochondrial genetic defect, with a consequent block of mitochondrial turnover and occurrence of premature cellular senescence in PARK2-PD fibroblasts, suggesting that these alterations represent potential mechanisms contributing to the loss of dopaminergic neurons.

Highlights

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, second only to Alzheimer’s disease
Previous data obtained on PARK2-PD fibroblasts harboring a compound heterozygous deletion in PARK2 displayed mitochondrial defects and Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC-1α) dysfunction [39], severe ultrastructural abnormalities, mainly in mitochondria and cytoskeleton [39,55], and altered expression level of several proteins involved in cytoskeleton structure dynamics, Ca2+ homeostasis, oxidative stress response protein and RNA processing [56,57]
Quantification using ImageJ software revealed a significant reduction of signal of about 20% and 70% in CTR2 and PARK2-PD, respectively (Figure 4F). These data indicate a reduction of the mitochondrial membrane potential in PARK2-PD cells. These results demonstrate that the discovered mitochondrial DNA (mtDNA) mutation is associated to mitochondrial dysfunction in PARK2-PD fibroblasts, and suggest that there is no compensatory activation of mitochondrial biogenesis as TFAM and other PGC-1α downstream target genes are downregulated or unchanged [39]

Summary

Introduction

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, second only to Alzheimer’s disease. PD is characterized by motor symptoms as bradykinesia, resting tremor, postural instability, and muscle rigidity together with non-motor signs such as anosmia, sleep disorders, depression and, with disease progression, dementia. The pathological mechanisms of PD are largely unknown, it has been established that multifactorial and genetic causes are involved. Correlated with monogenic mutations in 15 causative genes. Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) [4] or in the α-synuclein gene [5] are causes of PD autosomal dominant forms, whereas genes involved in autosomal recessive PD include parkin [6], PTEN-induced

Methods

Results

Conclusion