title: p62 Pathology Model in the Rat Substantia Nigra with Filamentous Inclusions and Progressive Neurodegeneration.
abstract: One of the proteins most frequently found in neuropathological lesions is the ubiquitin binding protein p62 (sequestosome 1). Post-mortem analysis of p62 is a defining diagnostic marker in several neurodegenerative diseases including amyotrophic lateral sclerosis and inclusion body myositis. Since p62 functions in protein degradation pathways including autophagy, the build-up of p62-positive inclusions suggests defects in protein clearance. p62 was expressed unilaterally in the rat substantia nigra with an adeno-associated virus vector (AAV9) in order to study p62 neuropathology. Inclusions formed within neurons from several days to several weeks after gene transfer. By electron microscopy, the inclusions were found to contain packed 10 nm thick filaments, and mitochondria cristae structure was disrupted, resulting in the formation of empty spaces. In corollary cell culture transfections, p62 clearly impaired mitochondrial function. To probe for potential effects on macroautophagy, we co-expressed p62 with a double fluorescent tagged reporter for the autophagosome protein LC3 in the rat. p62 induced a dramatic and specific dissociation of the two tags. By 12 weeks, a rotational behavior phenotype manifested, consistent with a significant loss of dopaminergic neurons analyzed post-mortem. p62 overexpression resulted in a progressive and robust pathology model with neuronal inclusions and neurodegeneration. p62 gene transfer could be a novel methodological probe to disrupt mitochondrial function or autophagy in the brain and other tissues in vivo.
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Kasey L
authors.initials: KL
authors.lastname: Jackson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States of America.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Dayton
authors.affiliation: Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Panchatcharam
authors.affiliation: Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.|Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McCarthy
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States of America.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Klein
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics* / Q000473:pathology*; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000071456:Sequestosome-1 Protein / Q000235:genetics* / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat