Peroxisomes: Biogenesis, Function, and Role in Human Disease

Foreword
Preface
Contents
Contributors
Part I: Biogenesis and Function of Peroxisome
	Chapter 1: The History of Peroxisomal Research
		1.1 Introduction
		1.2 Peroxisome Function
		1.3 Biogenesis of the Peroxisome
		1.4 Peroxisomal Diseases
		References
	Chapter 2: Peroxisome Biogenesis
		2.1 Introduction
		2.2 The Location Where the Pre-peroxisomes Are Formed and How They Mature into Peroxisomes
			2.2.1 Insertion of PMPs into the ER Membrane and Their Sorting to the Specific Domain
			2.2.2 Budding and Fusion of PPV
			2.2.3 The Elongation and Fission of Peroxisomes
		2.3 Peroxisomal Matrix Protein Targeting
			2.3.1 Cargo Recognition in the Cytosol
			2.3.2 Docking of Receptor-Cargo Complex at the Peroxisomal Membrane
			2.3.3 Cargo Translocation Across the Membrane
			2.3.4 Receptor Recycling
		2.4 Targeting of the Peroxisomal Membrane Proteins
		2.5 Organelle Selective Targeting of ABC Transporters
		2.6 Concluding Remarks
		References
	Chapter 3: Peroxisome Degradation and Its Molecular Machinery
		3.1 Pathways for the Degradation of Mammalian Peroxisomes and Their Components
			3.1.1 Lon Protease
			3.1.2 15-LOX
			3.1.3 Autophagy
		3.2 Molecular Machinery of Macroautophagy
			3.2.1 Identification of Autophagy-Related (ATG) Gene Products
			3.2.2 Functional Groups of ATG Gene Products
		3.3 Molecular Machinery of Peroxisome-Specific Autophagy (Pexophagy)
			3.3.1 Insights from Yeast Studies
			3.3.2 Molecular Machinery of Mammalian Pexophagy (1): Atg Proteins
			3.3.3 Molecular Machinery of Mammalian Pexophagy (2): Ubiquitin
		3.4 Medical and Physiological Aspects of Mammalian Pexophagy
			3.4.1 Peroxisomal Biogenesis Disorders and Pexophagy
			3.4.2 Oxygen, ROS and Pexophagy
		3.5 Future Perspectives
		References
	Chapter 4: The Function of the Peroxisome
		4.1 Outline of Peroxisome Function
		4.2 Peroxisome and Lipid Metabolism
			4.2.1 Transport of Substrate into Peroxisomes
			4.2.2 Fatty Acid β-Oxidation
			4.2.3 Fatty Acid α-Oxidation
			4.2.4 Ether-Phospholipid Synthesis
		4.3 Structure and Function of the ABC Transporter
			4.3.1 ABCD Transporters
			4.3.2 Structure of the ABCD Transporters
			4.3.3 Function of the ABCD Transporters
				4.3.3.1 ABCD1
				4.3.3.2 ABCD2
				4.3.3.3 ABCD3
				4.3.3.4 ABCD4
		4.4 Solute/Metabolite Traffic Across the Peroxisomal Membrane
			4.4.1 Non-selective Channels on the Peroxisomal Membrane
			4.4.2 The ATP and Cofactor Transporter
			4.4.3 The Export of Metabolites by β-Oxidation and the Degraded Cofactors
		4.5 Peroxisomes and Oxidative Stress
			4.5.1 Oxidative Stress and the Antioxidant Defence Systems
			4.5.2 Impact of Peroxisomal ROS Production on Mitochondrial Function
			4.5.3 Oxidative Stress-Related Signaling Pathways
			4.5.4 Oxidative Stress and Neurodegenerative Diseases
		4.6 Crosstalk Between the Peroxisome and Other Organelles
			4.6.1 Crosstalk Through Lipid Metabolites
				4.6.1.1 Mitochondria
				4.6.1.2 The ER
				4.6.1.3 Lysosomes
				4.6.1.4 Lipid Droplets
			4.6.2 Crosstalk During Antiviral Signalling
		4.7 Concluding Remarks
		References
Part II: Dysfunction of Peroxisome and Human Disease
	Chapter 5: Peroxisomal Disorders
		5.1 Introduction
		5.2 Peroxisome Biogenesis Disorders (PBD)
			5.2.1 Zellweger Spectrum Disorders
			5.2.2 Rhizomelic Chondrodysplasia Punctate Type 1 and 5
			5.2.3 Broad Phenotypes of Known PEX Gene Defects and Newly Identified Disease-Causing Genes
				5.2.3.1 Broad Phenotypes of PEX Gene Defects
				5.2.3.2 Mulibrey Nanism (TRIM37 Deficiency)
			5.2.4 Dysfunction of Peroxisomal Proliferation and Fission
				5.2.4.1 PEX11β Deficiency
				5.2.4.2 Encephalopathy Due to Defective Mitochondrial and Peroxisomal Fission 1 (EMPF1) (DNM1L Deficiency)
				5.2.4.3 Charcot-Marie-Tooth Disease Type 4A (GDAP1 Deficiency)
		5.3 Single Enzyme Deficiencies (SED)
			5.3.1 Impaired β-Oxidation of Fatty Acids
				5.3.1.1 Adrenoleukodystrophy (ALD)
				5.3.1.2 Acyl-CoA Oxidase 1 (ACOX1) Deficiency
				5.3.1.3 d-Bifunctional Protein (DBP) Deficiency
				5.3.1.4 Sterol Carrier Protein X (SCPx) Deficiency
				5.3.1.5 2-Methylacyl-CoA Racemase (AMACR) Deficiency
				5.3.1.6 Acyl-CoA-Binding Domain-Containing Protein 5 (ACBD5) Deficiency
			5.3.2 Impaired Bile Acids Synthesis
				5.3.2.1 Acyl-CoA Oxidase 2 (ACOX2) Deficiency
				5.3.2.2 Peroxisomal Membrane Protein, 70KD (PMP70) (ABCD3) Deficiency
				5.3.2.3 Bile Acid-CoA: Amino Acid N-Acyltransferase (BAAT) Deficiency
			5.3.3 Impaired α-Oxidation of Fatty Acids
				5.3.3.1 Phytanoyl-CoA Hydroxylase (PHYH) Deficiency (Refsum Disease)
			5.3.4 Impaired Plasmalogen Biosynthesis
			5.3.5 Impaired Hydrogen Peroxide Metabolism
				5.3.5.1 Catalase Deficiency (Acatalasemia, Hypocatalasemia)
			5.3.6 Impaired Glyoxylate Metabolism
				5.3.6.1 Hyperoxaluria Type 1 (Alanine: Glyoxylate Aminotransferase Deficiency)
				5.3.6.2 Glycolate Oxidase 1 (GOX1) Deficiency
		5.4 Adrenoleukodystrophy (ALD)
			5.4.1 Epidemiology and Phenotypes
				5.4.1.1 Childhood Cerebral ALD (CCALD)
				5.4.1.2 Adolescent Cerebral ALD (AdolCALD)
				5.4.1.3 Adrenomyeloneuropathy (AMN)
				5.4.1.4 Adult Cerebral ALD (ACALD)
				5.4.1.5 Olivo-Ponto-Cerebellar Type of ALD (OPCALD)
				5.4.1.6 Addison Only
				5.4.1.7 Symptomatic Female
			5.4.2 Diagnostic Methods
			5.4.3 Differential Diagnosis
				5.4.3.1 Diseases to Be Differentiated in ALD of Boys
				5.4.3.2 Diseases to Be Differentiated in ALD of Adults
			5.4.4 Treatment
			5.4.5 Presymptomatic Diagnosis and Newborn Screening
				5.4.5.1 Presymptomatic Diagnosis
				5.4.5.2 Newborn Screening (NBS)
			5.4.6 Pathophysiology
				5.4.6.1 Elucidated Facts and Unresolved Issues
				5.4.6.2 Task to Be Solved
			5.4.7 Current and Future Prospective
		5.5 Role of Peroxisome in Cancer and Age-Related Diseases
			5.5.1 Role of Peroxisomes in Neurodegenerative Diseases
			5.5.2 Role of Peroxisomes in Diabetes
			5.5.3 Role of Peroxisomes in Cancer
		References
	Chapter 6: Model Organisms for Understanding Peroxisomal Disorders
		6.1 Introduction
		6.2 Model Organisms for Peroxisome Biogenesis Disorder (PBD)
			6.2.1 PBD Mouse Models
			6.2.2 Pex KO Mice Lacking Peroxisomes in Whole Body: the Model for Zellweger Syndrome (ZS) (Pex2, Pex5, Pex13 KO Mouse)
			6.2.3 Conditional KO and Conditional Rescue in Mouse Models
			6.2.4 Other KO Mice (Pex1, Pex10, Pex11α, Pex11β)
			6.2.5 Models of Rhizomelic Chondrodysplasia Punctata (RCDP) Type 1
			6.2.6 PBD Zebrafish Models
			6.2.7 PBD Fruit Fly Models
		6.3 Model Organisms for Single Enzyme Deficiencies
			6.3.1 ACOX1 Deficiency Mouse Model
			6.3.2 D-BP Deficiency Mouse Model
			6.3.3 SCPx Deficiency Mouse Model
			6.3.4 GNPAT and AGPS Mutant Mice: RCDP Type 2 and Type3 Models
			6.3.5 X-ALD Model Mouse
			6.3.6 X-ALD Zebrafish Model
			6.3.7 AMACR Deficiency Mouse Model
		6.4 Conclusions
		References
	Chapter 7: Diagnosis of Peroxisomal Disorders
		7.1 Introduction
		7.2 A conventional Diagnostic System for Typical Cases of Peroxisomal Disorders
		7.3 An Advanced Diagnostic System for Broad Cases of Peroxisomal Disorders
			7.3.1 New Phenotypes of Known Pathogenic Genes Identified by NGS
			7.3.2 Newly Identified Peroxisomal Diseases by NGS
			7.3.3 Efficient Diagnostic System Combined Peroxisomal Metabolite Screening and NGS in Japan
		7.4 Diagnostic System for ALD
			7.4.1 Prompt Diagnostic System in Gifu University
			7.4.2 Presymptomatic Patients’ Diagnosis
		References
	Chapter 8: Therapeutic Strategies for X-Linked Adrenoleukodystrophy, a Representative Peroxisomal Disorder
		8.1 Introduction
		8.2 X-Linked Adrenoleukodystrophy (X-ALD)
		8.3 Hematopoietic Stem Cell Transplantation (HSCT)
			8.3.1 Allogeneic HSCT
			8.3.2 Ex Vivo Gene Therapy
			8.3.3 How Do Bone Marrow-Derived Macrophages Halt Inflammatory Demyelination?
			8.3.4 Newborn Screening for the Use of HSCT
		8.4 Pharmacological Treatment
			8.4.1 Lowering the VLCFA Level
				8.4.1.1 Early Studies
				8.4.1.2 Pharmacological Induction of ABCD2 Gene Expression
				8.4.1.3 Stimulation of Residual VLCFA β-Oxidation
				8.4.1.4 Stabilization of ABCD1 with a Missense Mutation
				8.4.1.5 Suppression of Excess Fatty Acid Elongation
		8.5 Suppression of Oxidative Stress
		8.6 Suppression of Inflammatory Processes
		8.7 Recent Studies of New Targets
			8.7.1 Blood-Brain Barrier
			8.7.2 Autophagy
			8.7.3 The Unfolded Protein Response
			8.7.4 The Development of Novel Drugs
		8.8 Concluding Remarks
		References
Part III: Topics in Peroxisome Research
	Chapter 9: The Isolation of Peroxisomes
		9.1 Introduction
		9.2 Isolation of Peroxisomes from the Rat Liver
			9.2.1 Procedure
			9.2.2 Results and Discussion
		9.3 Immuno-Isolation of Peroxisomes from the Rat Liver
			9.3.1 Procedure
			9.3.2 Results and Discussion
		9.4 Isolation of the Peroxisomal Membranes
			9.4.1 Procedure
			9.4.2 Results and Discussion
		9.5 Isolation of Peroxisomes from Cultured Mammalian Cells
			9.5.1 Procedure
			9.5.2 Results and Discussion
		9.6 Isolation of Peroxisomes from Komagataella phaffii
			9.6.1 Procedure
			9.6.2 Results and Discussion
		References
	Chapter 10: Structure Biology of Peroxisomal Proteins, Peroxins
		10.1 Introduction: Peroxisome Biogenesis and Structural Biology
		10.2 Structural Basis for the Recognition Mechanism of the Second Peroxisomal Targeting Signal, PTS2 by Its Receptor Complex Pex7p and Pex21p
			10.2.1 Preparation of Pex7p–Pex21pC–Fox3pN-MBP Complex
			10.2.2 The Structure of the Pex7p–Pex21pC–Fox3pN-MBP Complex
			10.2.3 Special Motif of Pex7p and Pex7p–Pex21p Complex Formation
			10.2.4 PTS2 Recognition by Cooperation of Pex7p and Pex21p
			10.2.5 In Vitro and In Vivo Assays of Pex7p and Pex21p Mutants Support Structural Interpretations
			10.2.6 Comparison with Mitochondrial Targeting Signal
		10.3 Structural Basis for Interactions Between Pex3p and Pex19p in Peroxisomes
			10.3.1 Definition of the Pex3p-Binding Region in Pex19p, for Use in Crystallization
			10.3.2 Overall Structure of the Pex3p Cytosolic Domain in Complex with the N-Terminal Pex19p Peptide
			10.3.3 Architecture of the Pex3p–Pex19p Interface
			10.3.4 Mutational Analysis of Functional Residues in Pex19p Required for Binding to Pex3p and for Peroxisome Biogenesis
			10.3.5 Proposed Mechanism for the PMP Translocation Process
		10.4 Future Prospect in Structural Biology Research of Peroxins (Outlook for Structural Biology of Peroxins)
		References
	Chapter 11: Lipidomics of Peroxisomal Disorders
		11.1 Introduction
		11.2 Lipid Species Affected in Peroxisomal Disorders
			11.2.1 Zellweger Syndrome (ZS), Neonatal Adrenoleukodystrophy (NALD) and Infantile Refsum’s Disease (IRD)
			11.2.2 X-ALD, Acyl-CoA Oxidase (AOX) Deficiency, D-bifunctional Protein (DBP) Deficiency and Acyl-CoA Binding Domain-Containing 5 (ACBD5) Deficiency
			11.2.3 Rhizomelic Chondrodysplasia Punctata (RCDP) Type-1, RCDP Type-2 and RCDP Type-3
			11.2.4 Refsum Disease, Sterol Carrier Protein X (SCPx) Deficiency and A-Methylacyl-CoA Racemase (AMACR) Deficiency
		11.3 Recent Advances in MS-Based Methods for Lipid Analysis
		11.4 Application of MS-Based Lipidomics in Peroxisomal Disorders
		11.5 Concluding Remarks
		References
	Chapter 12: Neurophysiology and Neuropsychology in Adrenoleukodystrophy (ALD)
		12.1 Neurophysiology and Neuropsychology as Noninvasive Methods for Early Identification of X Linked-Adrenoleukodystrophy (X-ALD) and Useful Follow-Up Procedure
		12.2 Neurophysiology of ALD
			12.2.1 Electroencephalography (EEG)
			12.2.2 Evoked Potentials (EPs)
				12.2.2.1 Auditory Brainstem Response (ABR)
				12.2.2.2 Visual Evoked Potential (VEP)
				12.2.2.3 Somatosensory Evoked Potential (SEP)
				12.2.2.4 Multimodal Evoked Potentials
				12.2.2.5 Transcranial Magnetic Stimulation (TMS)
				12.2.2.6 Event Related Potential (ERP)
				12.2.2.7 Summary of Neurophysiological Examination in ALD
		12.3 Neuropsychology of X-ALD
			12.3.1 What Is Neuropsychology?
			12.3.2 Application of Neuropsychology to ALD
			12.3.3 Neuropsychological Tests
				12.3.3.1 Wechsler Intelligence Scale Tests
				12.3.3.2 Other Neuropsychological Tests
				12.3.3.3 Neuropsychology in Children with ALD
				12.3.3.4 Auditory Agnosia in Children with ALD (Furushima et al. 2015)
				12.3.3.5 Summary of Neuropsychological Tests in ALD
		References