Pennsylvania Folklife Vol. 38, No. 3

• The Wayside Inn • A Draft Board in World War I • The Compass Inn: A Stagecoach Era Legacy • The Pennsylvania German Dialect Playwriting Contests of 1941, 1942, 1983 and 1986 • Aldes un Neies (Old and New)https://digitalcommons.ursinus.edu/pafolklifemag/1123/thumbnail.jp

Different proteolipid protein mutants exhibit unique metabolic defects

PMD (Pelizaeus–Merzbacher disease), a CNS (central nervous system) disease characterized by shortened lifespan and severe neural dysfunction, is caused by mutations of the PLP1 (X-linked myelin proteolipid protein) gene. The majority of human PLP1 mutations are caused by duplications; almost all others are caused by missense mutations. The cellular events leading to the phenotype are unknown. The same mutations in non-humans make them ideal models to study the mechanisms that cause neurological sequelae. In the present study we show that mice with Plp1 duplications (Plp1tg) have major mitochondrial deficits with a 50% reduction in ATP, a drastically reduced mitochondrial membrane potential and increased numbers of mitochondria. In contrast, the jp (jimpy) mouse with a Plp1 missense mutation exhibits normal mitochondrial function. We show that PLP in the Plp1tg mice and in Plp1-transfected cells is targeted to mitochondria. PLP has motifs permissive for insertion into mitochondria and deletions near its N-terminus prevent its co-localization to mitochondria. These novel data show that Plp1 missense mutations and duplications of the native Plp1 gene initiate uniquely different cellular responses

Increased Plp1 gene expression leads to massive microglial cell activation and inflammation throughout the brain

PMD (Pelizaeus–Merzbacher disease) is a rare neurodegenerative disorder that impairs motor and cognitive functions and is associated with a shortened lifespan. The cause of PMD is mutations of the PLP1 [proteolipid protein 1 gene (human)] gene. Transgenic mice with increased Plp1 [proteolipid protein 1 gene (non-human)] copy number model most aspects of PMD patients with duplications. Hypomyelination and demyelination are believed to cause the neurological abnormalities in mammals with PLP1 duplications. We show, for the first time, intense microglial reactivity throughout the grey and white matter of a transgenic mouse line with increased copy number of the native Plp1 gene. Activated microglia in the white and grey matter of transgenic mice are found as early as postnatal day 7, before myelin commences in normal cerebra. This finding indicates that degeneration of myelin does not cause the microglial response. Microglial numbers are doubled due to in situ proliferation. Compared with the jp (jimpy) mouse, which has much more oligodendrocyte death and hardly any myelin, microglia in the overexpressors show a more dramatic microglial reactivity than jp, especially in the grey matter. Predictably, many classical markers of an inflammatory response, including TNF-α (tumour necrosis factor-α) and IL-6, are significantly up-regulated manyfold. Because inflammation is believed to contribute to axonal degeneration in multiple sclerosis and other neurodegenerative diseases, inflammation in mammals with increased Plp1 gene dosage may also contribute to axonal degeneration described in patients and rodents with PLP1 increased gene dosage

Robert P. Skoff abstract 1

abstract: Thymidine determination of neuroglial origin in rat optic nerve: a light and electron microscope autoradiographic studyCorrespondenc

Robert P. Skoff resume 1

resumeCorrespondenc

Robert P. Skoff to W. Maxwell Cowan, November 17, 1970

Inquiry regarding possible positionCorrespondenc

Robert P. Skoff to Viktor Hamburger, November 27, 1974

reprint enclosed in letterCorrespondenc

Robert P. Skoff to Viktor Hamburger, September 15, 1976

Request for reccomendation for grantCorrespondenc

Robert P. Skoff to Viktor Hamburger, February 16, 1971

Thank you for visit. Plans to use electron microscopeCorrespondenc

Robert P. Skoff abstract, 1970

abstract: Morphology of labelled cells in degenerating rat optic nerveCorrespondenc