ABSTRACT
The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease.
Subject(s)
Behavior, Animal , Cerebellar Ataxia/enzymology , Cerebellum/enzymology , Mitochondrial Proteins/deficiency , Muscle, Skeletal/enzymology , Ubiquinone/deficiency , Animals , COS Cells , Cerebellar Ataxia/genetics , Cerebellar Ataxia/physiopathology , Cerebellar Ataxia/psychology , Cerebellum/physiopathology , Cerebellum/ultrastructure , Chlorocebus aethiops , Disease Models, Animal , Exercise Tolerance , Female , Genetic Predisposition to Disease , HEK293 Cells , Humans , Lipid Metabolism , Male , Maze Learning , Mice, Inbred C57BL , Mice, Knockout , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/genetics , Models, Molecular , Motor Activity , Muscle Strength , Muscle, Skeletal/physiopathology , Phenotype , Protein Binding , Protein Conformation , Proteomics/methods , Recognition, Psychology , Rotarod Performance Test , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Seizures/enzymology , Seizures/genetics , Seizures/physiopathology , Structure-Activity Relationship , Time Factors , Transfection , Ubiquinone/chemistry , Ubiquinone/geneticsABSTRACT
Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Finally, we outline some of the therapeutic strategies that are currently being pursued to slow down the disease.
Subject(s)
Huntington Disease/genetics , Huntington Disease/pathology , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Gene Expression Regulation , Humans , Huntingtin Protein/chemistry , Huntingtin Protein/genetics , Huntington Disease/therapy , Nerve Tissue Proteins/chemistry , Nuclear Proteins/chemistry , Trinucleotide RepeatsABSTRACT
Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knockout studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation as well as other roles, including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases. Finally, we describe how autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions and consider possible pathways and druggable targets that may be suitable for this objective.
Subject(s)
Autophagy/physiology , Lysosomes/metabolism , Motor Neurons/pathology , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/therapy , Signal Transduction/physiology , Animals , Humans , Neurodegenerative Diseases/metabolism , Proteins/metabolismABSTRACT
Coenzyme Q (CoQ), also known as ubiquinone, is an essential lipophilic molecule present in all cellular membranes and involved in a variety of cellular functions, in particular as an electron carrier in the mitochondrial respiratory chain and as a potent antioxidant. CoQ is synthesized endogenously through a complex metabolic pathway involving over 10 different components. Primary CoQ10 deficiency in humans, due to mutations in genes involved in CoQ biosynthesis, is a heterogeneous group of rare disorders presenting severe and complex clinical symptoms. The generation of mouse models deficient in CoQ is important to further clarify the cellular function of CoQ and to unravel the complexity in the pathophysiological consequences of CoQ deficiency. This review summarizes the current knowledge on mouse models of primary CoQ deficiency.
ABSTRACT
Coenzyme Q, or ubiquinone, is an endogenously synthesized lipid-soluble antioxidant that plays a major role in the mitochondrial respiratory chain. Although extensively studied for decades, recent data on coenzyme Q have painted an exciting albeit incomplete picture of the multiple facets of this molecule's function. In humans, mutations in the genes involved in the biosynthesis of coenzyme Q lead to a heterogeneous group of rare disorders, with most often severe and debilitating symptoms. In this review, we describe the current understanding of coenzyme Q biosynthesis, provide a detailed overview of human coenzyme Q deficiencies and discuss the existing mouse models for coenzyme Q deficiency. Furthermore, we briefly examine the current state of affairs in non-mitochondrial coenzyme Q functions and the latter's link to statin.