The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease

Understanding the function of genes mutated in hereditary forms of Parkinson’s disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson’s disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson’s disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin’s E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss

Increase in muscle mitochondrial biogenesis does not prevent muscle loss but increased tumor size in a mouse model of acute cancer-induced cachexia.

Cancer-associated cachexia is a complex metabolic condition characterized by the progressive loss of body fat and deterioration of muscle mass. Although the cellular and molecular mechanisms of cachexia are incompletely understood, previous studies have suggested mitochondrial dysfunction in murine models of cancer cachexia. To better understand the metabolic shift in cancer-induced cachexia, we studied the effects of enhanced oxidative capacity on muscle wasting using transgenic mice over-expressing Peroxisome Proliferator-Activated Receptor gamma Co-activator-1α (PGC-1α) in skeletal muscle in a Lewis lung carcinoma-implanted model. Increased mitochondrial biogenesis was observed in the skeletal muscle of tumor-implanted mice. However, these increases did not prevent or reverse muscle wasting in mice harboring tumors. Moreover, tumor size was increased in muscle PGC-1α over-expressing mice. We found similar levels of circulating inflammatory cytokines in tumor-implanted animals, which was not affected by increased muscle expression of PGC-1α. Our data indicated that increased mitochondrial biogenesis in skeletal muscle is not sufficient to rescue tumor-associated, acute muscle loss, and could promote tumor growth, possibly through the release of myokines

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Regional susceptibilities to mitochondrial dysfunctions in the CNS

Mitochondrial dysfunctions are very common features of age-related neurological diseases such as Parkinson's, Alzheimer's and Huntington's disease. Several studies have shown that bioenergetic impairments have a major role in the degeneration of the central nervous system (CNS) in these patients. Accordingly, one of the main symptoms in many mitochondrial diseases is severe encephalopathy. The heterogeneity of the brain in terms of anatomic structures, cell composition, regional functions and biochemical properties makes the analysis on this organ very complex and difficult to interpret. Humans, in addition to animal models, exposed to toxins that affect mitochondrial function, in particular oxidative phosphorylation, exhibit degeneration of specific regions within the brain. Moreover, mutations in ubiquitously expressed genes that are involved in mitochondrial function also induce regional-specific cell death in the CNS. In this review, we will discuss some current hypotheses to explain the regional susceptibilities to mitochondrial dysfunctions in the CNS

Mouse models of Parkinson's disease associated with mitochondrial dysfunction

Despite years of intensive research, the understanding of Parkinson's disease (PD) is still rudimentary. Genetic causes of rare familial cases have offered venues of investigation, and interestingly, have strengthened the case for a mitochondrial dysfunction in the pathogenesis of PD. Mouse models, where these and other mitochondrial-related genes are affected are helping not only in understanding PD, but also in providing a powerful tool to test therapeutics. In this review, we will discuss the different characteristics of these mouse models. This article is part of a Special Issue entitled ‘Mitochondrial function and dysfunction in neurodegeneration’

The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation

The multiple dysfunctional changes associated with a brain affected with Alzheimer's disease (AD) makes the understanding of primary pathogenic mechanisms challenging. Mitochondrial dysfunction has been associated with almost every neurodegenerative disease and neurodegenerative-related event. Alzheimer's disease is no exception with data suggesting mitochondrial malfunctions ranging from improper organelle dynamics, defective oxidative phosphorylation (OXPHOS), oxidative stress, and harmful beta amyloid (Abeta) associations with the mitochondria. A major change often associated with AD is impairment of the electron transport chain at complex IV: cytochrome c oxidase (COX). This mini-review concentrates on recent work by our group that sheds light on the role COX deficiency plays in the pathophysiology of AD using a transgenic mouse model. Results suggest that neuronal COX deficiency does not increase oxidative stress and nor increases amyloidal formations in vivo. Conclusions from this work also suggest that Abeta formation is a cause of COX deficiency as opposed to the consequence

The Imbalance of Astrocytic Mitochondrial Dynamics Following Blast-Induced Traumatic Brain Injury

Mild blast-induced traumatic brain injury (bTBI) is a modality of injury that has been of major concern considering a large number of military personnel exposed to explosive blast waves. bTBI results from the propagation of high-pressure static blast forces and their subsequent energy transmission within brain tissue. Exposure to this overpressure energy causes a diffuse injury that leads to acute cell damage and, if chronic, leads to detrimental long-term cognitive deficits. The literature presents a neuro-centric approach to the role of mitochondria dynamics dysfunction in bTBI, and changes in astrocyte-specific mitochondrial dynamics have not been characterized. The balance between fission and fusion events is known as mitochondrial dynamics. As a result of fission and fusion, the mitochondrial structure is constantly altering its shape to respond to physiological stimuli or stress, which in turn affects mitochondrial function. Astrocytic mitochondria are recognized to play an essential role in overall brain metabolism, synaptic transmission, and neuron protection. Mitochondria are vulnerable to injury insults, leading to the increase in mitochondrial fission, a mechanism controlled by the GTPase dynamin-related protein (Drp1) and the phosphorylation of Drp1 at serine 616 (p-Drp1s616). This site is critical to mediate the Drp1 translocation to mitochondria to promote fission events and consequently leads to fragmentation. An increase in mitochondrial fragmentation could have negative consequences, such as promoting an excessive generation of reactive oxygen species or triggering cytochrome c release. The aim of the present study was to characterize the unique pattern of astrocytic mitochondrial dynamics by exploring the role of DRP1 with a combination of in vitro and in vivo bTBI models. Differential remodeling of the astrocytic mitochondrial network was observed, corresponding with increases in p-Drp1S616 four hours and seven days post-injury. Further, results showed a time-dependent reactive astrocyte phenotype transition in the rat hippocampus. This discovery can lead to innovative therapeutics targets to help prevent the secondary injury cascade after blast injury that involves mitochondria dysfunction